How can I create an orthographic render similar to the Portal 2 promotional videos? Some of the Portal and Portal 2 promotional videos have a 2D/3Dish world in an orthographic/isometric view. 

I know how to set the camera to orthographic in Blender, but how would I go about creating the 2D-style characters? Also, which render engine should I use? Any tips on how to create something similar would be appreciated.

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It's not clear on what aspects your question is focussed. For this orthographic render I used BI since freestyle isn't available when using cycles. The caracters were made from a plane with a few extrusions and a circle.



Enable freestyle in the render tab :



To control which objects get outline,  create a group (here desk and sitting guy) after that go to the Render Layers Tab select the group in the highlighted box (red).



If you want to use cycles you might be interested in blender-cycles-toon-material-node-setup