I already have a complete HTML/CSS mockup should I use a base theme or start from scratch? Will it be less painful to just build my theme from scratch using the HTML/CSS mockup that I have or should I still go through the process of using a base theme like Zen?
It's a mix of personal preference, familiarity with the theme system and, arguably most importantly, the experience of the end-user admin and how much they'll need to modify layout.

Unless the site layout will need to be extensively modified (by a non-developer, beyond just toggling/placing blocks) I would always choose to start from scratch.