In the history of science, provocative but, at times, controversial ideas have been put forward to explain basic problems that confront and intrigue the scientific community. These hypotheses, although often not correct in every detail, lead to increased discussion that ultimately guides experimental tests of the principal concepts and produce valuable insights into long-standing questions. Here, we present a hypothesis, the "H3 barcode hypothesis." Hopefully, our ideas will evoke critical discussion and new experimental approaches that bear on general topics, such as nuclear architecture, epigenetic memory, and cell-fate choice. Our hypothesis rests on the central concept that mammalian histone H3 variants (H3.1, H3.2, and H3.3), although remarkably similar in amino acid sequence, exhibit distinct posttranslational "signatures" that create different chromosomal domains or territories, which, in turn, influence epigenetic states during cellular differentiation and development. Although we restrict our comments to H3 variants in mammals, we expect that the more general concepts presented here will apply to other histone variant families in organisms that employ them.