The hypothesis of the evolutionary origin of bipolar disorder (EOBD) synthesized ideas about the biological clock and seasonal shifts in mood (Rosenthal, Wehr) with theorizing that bipolar disorder descends from a pyknic (compact, cold-adapted) group (Kretchmer). The hypothesis suggested that bipolar behaviors evolved in the northern temperate zone as highly derived adaptations to the selective pressures of severe climatic conditions during the Pleistocene. Given evidence of Neandertal contributions to the human genome, the hypothesis is extended (EOBD-R) to suggest Neandertal as the ancestral source for bipolar vulnerability genes (susceptibility alleles). The EOBD-R hypothesis explains and integrates existing observations: bipolar disorder has the epidemiology of an adaptation; it is correlated with a cold-adapted build, and its moods vary according to light and season. Since the hypothesis was first published, data consistent with it have continued to appear. Individuals with seasonal affective disorder, which is related to bipolar disorder, have been shown to manifest a biological signal of season change similar to that found in hibernating animals. The involvement of the circadian gene network in the pathophysiology of bipolar disorder has been confirmed. Because selective pressures during the Pleistocene would have been greatest for women of reproductive age, they are expected to manifest winter depression more than males or younger females, which is the case. (This sex difference is also found in hibernating mammals.) Because it is hypothesized that the evolution of bipolar disorder took place in the northern temperate zone during the Pleistocene, it is not expected that individuals of African descent, lacking Neandertal genes, will manifest circular bipolar I disorder, and in fact, the incidence of bipolar disorder among black individuals is less than among whites. A definitive test of the hypothesis is proposed: It is predicted that the bipolar and Neandertal genomes will be more similar than the modern human and Neandertal genomes, and the modern human and San and Yoruba genomes will be more similar than the bipolar and San and Yoruba genomes. Failure to confirm these predictions will falsify the EOBD-R hypothesis. The EOBD-R hypothesis has important implications in the search for bipolar vulnerability genes and our understanding of ourselves and our Neandertal ancestor. At a practical level, confirmation of the EOBD-R hypothesis will boost interest and research in the prevention and management of bipolar symptoms by manipulation of ambient light.