I normally choose the hilliest routes I can find. When I decided to ride down to Coventry from Hebden Bridge in 2007, I did a tour of the local hills first, before tackling Holme Moss and Snake Pass and then I went over lots more Peak District hills to get off the main roads.
I would only choose the flat route if the weather had turned awful, or I was ill, or injured. Oh, or my bike was damaged so I couldn't select my low gears. (Actually, if the gears were broken, I'd be tempted to fix it in bottom gear and go by the hills anyway and just freewheel on the descents.)