The first main issue was the arc_shrink_shift default being poor for machines with a large ARC. Our machines have Arc at several 100GB, so the default arc_shrink_shift was flushing several GBs to disk at a time. This was causing our machines to become unresponsive for several seconds at a time pretty frequently.
The other main issue we encountered was when we tried to delete lots of data at a time. We aren't sure why, but when we tried to delete a lot of data (~200GB from each machine which each contain several TB of data), our databases become unresponsive for an hour.
Other then these issues, ZFS has worked incredibly well. The builtin compression has saved us lots of $$$. It's just the unknown unknowns that have been getting us.