The reasons why certain domains evolve much slower than others is unclear. The notion that functionally more important genes evolve more slowly than less important genes is one of the few commonly believed principles of molecular evolution. The macro-domain (also known as the X domain) is an ancient, slowly evolving and highly conserved structural domain found in proteins throughout all of the kingdoms and was first discovered nearly two decades ago with the isolation and cloning of macroH2A1. Macrodomains, which are functionally promiscuous, have been studied intensively for the past decade due to their importance in the regulation of cellular responses to DNA damage, chromatin remodeling, transcription and tumorigenesis. Recent structural, phylogenetic and biological analyses, however, suggest the need for some reconsideration of the evolutionary advantage of concentrating such a plethora of diverse functions into the macrodomain and of how macrodomains could perform so many functions. In this article, we focus on macrodomains that are evolving slowly and broadly discuss the potential relationship between the biological evolution and functional diversity of macrodomains.