Silencing requires particular lysines in the extended amino-terminal tail of histones H3 and H4 (Thompson et al. 1994Hecht et al. 1995;Braunstein et al. 1996). These and other lysines of the tail are acetylated in active chromatin but deacetylated in silenced chromatin (Braunstein et al. 19931996). The deacetylated histones evidently can fold into a more compact, closed nucleosomal structure (Luger et al. 1997). These considerations led to the suggestion that Sir2 could be a histone deacetylase. Further evidence for this claim arose from the global deacetylation of yeast histones observed when Sir2 was overexpressed (Braunstein et al. 1993). However, attempts to demonstrate a histone deacetylase activity by Sir2 in vitro initially met with failure.