Best approach for a minimal HTML5 theme for Drupal
Less or SCSS are not that dissimilar to CSS (since they compile down to CSS anyway), they just have some additional features (such as mixins) and have in some cases a nicer layout. I personally have used scss and Compass to compile my scss, and also for the ability to include resets and things automatically without having to add in your own reset.css file.

In terms of learning Drupal themes, you have a choice, either use something like the omega base theme and subtheme that, or alternatively start from scratch with a clean, empty folder with the following in it:

exampletheme/
    css/
    templates/
    js/
    exampletheme.info
    template.php


And build up from there. The existing themes, whilst good for some information, are very content-heavy (by virtue of being mature, complex themes). Use a browser such as chrome/firefox with firebug in order to find out what elements are tagged or classed as. The drupal.org theme guide and the specific section on d6 &amp; d7 is quite a good place to start.

As far as grid frameworks, I started using 960 grid as that was something which conceptually struck a chord with me. They all have similar features, though the way they work in practice is different.