In eukaryotic cells, mRNAs are exquisitely controlled, often through regulatory elements in their 3' untranslated regions (3'UTRs). Proteins that bind to those sites are key players in controlling mRNA stability, translation and localization. One family of regulatory proteins--the PUF proteins--are not only structurally related, but also bind to 3'UTRs and modulate mRNA expression in a wide variety of eukaryotic species. They do so either by enhancing turnover or repressing translation, and act combinatorially with other regulatory proteins. Here, we discuss the evolution, biological function and mechanisms of action of the PUF protein family, and suggest that a primordial function of PUF proteins is to sustain mitotic proliferation of stem cells.