The BTB domain is a protein–protein interaction motif that is found throughout eukaryotes. It determines a unique tri‐dimensional fold with a large interaction surface. The exposed residues are highly variable and can permit dimerization and oligomerization, as well as interaction with a number of other proteins. BTB‐containing proteins are numerous and control cellular processes that range from actin dynamics to cell‐cycle regulation. Here, we review findings in the field of transcriptional regulation to illustrate how the high variability of the BTB has allowed related transcription factors to evolve different functional abilities. We then report how recent work has showed that, in spite of their high sequence divergence and apparently unrelated functions, many BTB‐containing proteins have at least one shared role: the recruitment of degradation targets to E3 ubiquitin ligase complexes. Taken together, these findings illustrate diverse and convergent functions of a versatile protein–protein interaction domain. BioEssays 28: 1194–1202, 2006. © 2006 Wiley Periodicals, Inc.