Been running it 7 years with a combined adlist of 1,089,320 domains.
It's really rare that I run into a site that won't load or function correctly (like once maybe twice a year). The most noticeable really is the ad results in Google, but I've moved away from that to DuckDuckGo anyway.
In the few cases that you do want to use a blocked doman; you can open pihole and either whitelist the domain with one click right out the query log, or disable pihole blocking entirely for 5sec-30min with one or two clicks.
If you really want to, you can group clients and adlists so some clients have much stricter blocking than others do. You can even leave some devices completely free of blocking while still using pihole to log their traffic.
By far one of the noisiest blocked domains is Nvidias driver telemetry. If you don't strip it out using NVSlimmer, it'll constantly retry its phone home, spamming the pihole with dns requests (not enough that it can't handle, but enough that it's VERY noticeable in the dashboard)