Oh, shit, I am the only person browsing news.yc who doesn't know about uBlock Origin, and I am so fscking excited!! I've installed this and have no idea how to use it so I'm about to dip into uBlock Matrix instead wish me luck~
uBlock I run with near-zero configuration tweaks, only enabling a few additional lists.
uMatrix I run in a much more restrictive mode (block all 3rd party, along with first party scripts and XHRs). Then I selectively unblock to unbreak sites.
In this way, uMatrix is my primary line of defense, and uBlock is a backup, in case I accidentally unblock an ad/malware domain when trying to unbreak a site. It also allows me to temporarily allow all with uMatrix if I just want a site to work, without enabling ads, etc.
That's exactly what I do too. You get better at knowing the likely candidates for what you need to unblock, but payment on a new site (or a modified since you last used it site) can be annoying.
Incidentally it has also led to me being both undercharged (client-side upping of the price wrt quantity) and double charged ('failed' transaction, unblock something, try again, turned out they actually both went through).
Huge pain, but it's fun.