For instance, I don't want either program to find files that end in *.pyc. I'm sure I can do this somehow using regexes or globs, but is there a way to make locate just ignore the files altogether? It's highly doubtful that I would ever want to search for a pyc file.
In updatedb.conf, uncomment the PRUNENAMES line and add the extension .pyc. On my Ubuntu system by default it reads:
# PRUNENAMES=".git .bzr .hg .svn"
Change it to
PRUNENAMES=".git .bzr .hg .svn .pyc"