Edit .htaccess yes, for Drupal, no. Drupal has its own extensive mechanisms for URL re-writing. I think you can do what you want, just be aware that you need to coordinate this so that Drupal starts working on the path after you tweak it. However… If you tweak the path from mysite/blog to blog.mysite, then Drupal doesn’t know what page you want.
In addition to trying to get a response here, I suggest you make inquiries at Drupal.org, and/or with a local community group of Drupal users. In the southern California area where DH is based, for example, there are a few groups that meet periodically, and people there participate in various specialty groups at groups.drupal.org. I think you’ll find the answers you need somewhere among the various resources available.