All you need is a consistent architecture and good planning. I think getting started on a HTML5 foundation is a good beginning. I suggest you build your project on a subtheme based on Omega or Fusion Theme kits.
Omega has a based on 960 grid system (12,18,24 columns, 20px gutter). It uses the zone/region relationship for a better block handling. Of course is a responsive theme, it starts mobile to desktop (not viceversa) which is very good.
You can even copy Omega subtheme page layout settings, alter it and save it under a new template with Delta module (created by Jake Strawn). Your settings can be then used in various context using the Context Module.
This is a good architecture to start with.
As a UX designer keep in mind Drupal is jQuery and jQuery UI ready, so learn to manipulate widgets via a module or a js (added in your info file).
Keep a consistent architecture and never mess with modules that are not necessary and only bloats your site.
In additional a good knowledge of Views module, contextual filters and relationships is a must.