It is now becoming apparent that cross‐talk between two protein lysine modifications, acetylation and ubiquitination, is a critical regulatory mechanism controlling vital cellular functions. The most apparent effect is the inhibition of proteasome‐mediated protein degradation by lysine acetylation. Analysis of the underlying mechanisms, however, shows that, besides a direct competition between the two lysine modifications, more complex and indirect processes also connect these two signalling pathways. These findings point to protein lysine acetylation as a potential regulator of various cellular functions involving protein ubiquitination. BioEssays 27:408–415, 2005. © 2005 Wiley periodicals, Inc.