After almost 10 years, I'm back to CB. And firstly, let me say, WOW, you guys have done an amazing job with the new developments.

Welcome back! Glad you like were CB is heading we've even more planned with CB 3.x being a complete modern rewrite of CB. The plan is to start CB 3.x development in parallel with CB 2.x once Joomla 4 has officially released.

Everything looks amazing, right down to the new beard on Kyle (which I don't remember, but amazing nonetheless).

What are the best Global Config settings, specifically SEO Settings and SEF URL's that will accommodate a fully loaded CB website?

I recommend the following.

Search Engine Friendly URLs: Yes
Use URL Rewriting: Yes

Depending on the language of the site you may need to set the following as well.

Unicode Aliases: Yes

I remember I used to have sporadic problems with SEF enabled and it's hard to change these settings once you get rolling.

We've addressed SEF rewrite issues starting with release CB 2.0. Plugins can actually have their own rewrite rules and they do in plugins like CB GroupJive and a few others that need rewrite rules.

Is SEF worth enabling or has Google figured it out?

Google has figured it out, but you'll still be scored lower for a non-SEF URL. So it will hurt SEO if you use non-SEF. It's also easier for users themselves to remember/share SEF URLs.