It is possible to create very large, complex building models using DesignBuilder but you should consider what you're trying to achieve by your modelling exercise before diving in and including every detail of the building design. Otherwise you may find you have created a beautiful model which is impractical to simulate because it takes too long or causes the simulation engine to fail. You should consider the following points.

EnergyPlus simulations are slowed down by: Lots of windows Lots of zones Lots of windows per zone Lots of surfaces Radiant heating systems Calculated natural ventilation using the Airflow Network Calculating solar reflections Reading hourly or sub-hourly results for extended simulation periods Not enough computer memory (RAM) Lots of output (quantity of data and number of reports) Lots of timesteps per hour

Note: You can speed up modelling, and in particular the drawing and deleting of partitions in large models, by switching off Automatic block zoning option.

You can speed up simulations by using these techniques:

1. Reduce the number of windows in the model by increasing the Window spacing. Shading issues aside, modelling a small number of large Windows has the same effect as a large number of small Windows provided you get the frame area right.
2. Avoid unnecessary wiggles and indents in block perimeters and partitions - keep it as simple as possible. The larger the model the more important it is to follow this advice. Where an indent in the perimeter gives shading then you could instead model this using a single flat surface without indent and use local shading devices with sidefins to model local window shading.
3. Use the Lump similar windows on surface option to speed up simulations with many similar windows per surface. Note that switching this option on has no effect for zones using Daylight lighting control or if the Full interior and exterior solar distribution option is selected.
4. Wherever possible lump similar adjacent zones together. Only create zones to model areas of the building with specific environmental conditions, and HVAC systems or internal gains schedules. A common mistake made by the beginners is to model each room as a separate zone. This is often not necessary for building energy simulations because many rooms will have reasonably similar operating conditions. In this case you may want to use one of the DesignBuilder Merging features to reduce the number of zones.
5. If there are multiple identical zones then you can use the Zone multiplier to reduce the number of zones processed.
6. When you first create a building model you may want to carry out simulations before partitioning the blocks into zones. If your un-partitioned blocks are very large there could be an enormous number of windows in the single zone making up a block and this can slow down EnergyPlus simulations especially if carrying out daylighting analysis. In this case you should try to reduce the number of windows in the model as recommended above.
7. Try to use the smallest number of blocks possible to keep the number of surfaces down.
8. Exclude semi-exterior unconditioned zones from the model and replace them with an R-Value.
9. Use Simple, (convective heating) HVAC descriptions.
10. Use the Scheduled Natural ventilation option.
11. Switching off calculation of solar reflections in the Model options dialog
12. Restricting hourly and sub-hourly results to short simulations for investigation of detailed building operation. You should not attempt to generate hourly or sub-hourly results for long periods (such as a whole year) unless your model is simple.
13. If you are interested in analysing a single zone within a much larger model, you could consider using the single zone option to carry out simulations just on the zone, excluding consideration of the rest of the building.
14. If you want to model a only a group of zones then you can exclude unnecessary zones by unchecking the Include zone model option.
15. Fit as much memory (RAM) to your computer as possible (2-4 GB ideally). Paging memory to disk during simulations of large models can cause EnergyPlus to grind to a halt.
16. Uncheck the Allow custom outputs option to speed output variable processing. 
17. Only request the output you really need. This will speed up simulation initialisation and reading of output (especially hourly and sub-hourly) at the end. If you are only looking at hourly results then you can get noticeably faster initialisation and simulations by switching off monthly and daily results. For example, simulation times for a test winter week simulation on a real model were: 
    1. - With hourly, daily, monthly outputs: 39 min
    2. - Only hourly outputs: 14 min
    3. - Only hourly outputs and checking 'Internal surface as adiabatic': 12 min
18. If you don't need surface data (Walls, Windows etc. heat transfer) switch the Surface heat transfer incl solar output option off.
19. Restricting hourly and sub-hourly results to short simulations for investigation of detailed building operation. Note that if you request large volumes of hourly or sub-hourly data this can result is a program crash when results are being loaded into DesignBuilder. To avoid this you should switch off automatic loading of EnergyPlus results to DesignBuilder and view results instead using the Results Viewer.
20. It is sometimes possible to use less timesteps per hour to speed up simulations. Some models can give reliable results using 2 timesteps per hour, however when complex Compact HVAC systems are being modelled, 4, 6 or even 10 timesteps may be required. If you aren't sure, compare the hourly results you obtain when using a range of timesteps per hour values and choose the minimum value that gives results equivalent to the 6 or 10 timesteps case.
21. If all else fails then you can model very large buildings by splitting them into smaller units and summing results outside DesignBuilder.