I've put together a custom website template on top of a responsive framework like HTML5 Boilerplate or Zurb Foundation or Bootstrap and it worked quite well. I used Jochem Bokker's Boilerplate SiteFinity theme
work as my starting point:
Here is a link to my responsive SiteFinity template conversation thread
with Jochem, I learned quite a bit in the process.
Once you get all the standard load order and pathname and JQuery version conflict bugs worked out it all behaves very predictably. It's simply a matter of understanding SiteFinity's design settings really well and also knowing the framework.