Molecular clocks have been used to date the divergence of humans and chimpanzees for nearly four decades. Nonetheless, this date and its confidence interval remain to be firmly established. In an effort to generate a genomic view of the human-chimpanzee divergence, we have analyzed 167 nuclear protein-coding genes and built a reliable confidence interval around the calculated time by applying a multifactor bootstrap-resampling approach. Bayesian and maximum likelihood analyses of neutral DNA substitutions show that the human-chimpanzee divergence is close to 20% of the ape-Old World monkey (OWM) divergence. Therefore, the generally accepted range of 23.8 -35 millions of years ago for the ape-OWM divergence yields a range of 4.98 -7.02 millions of years ago for human-chimpanzee divergence. Thus, the older time estimates for the human-chimpanzee divergence, from molecular and paleontological studies, are unlikely to be correct. For a given the ape-OWM divergence time, the 95% confidence interval of the human-chimpanzee divergence ranges from ؊12% to 19% of the estimated time. Computer simulations suggest that the 95% confidence intervals obtained by using a multifactor bootstrapresampling approach contain the true value with >95% probability, whether deviations from the molecular clock are random or correlated among lineages. Analyses revealed that the use of amino acid sequence differences is not optimal for dating humanchimpanzee divergence and that the inclusion of additional genes is unlikely to narrow the confidence interval significantly. We conclude that tests of hypotheses about the timing of human-chimpanzee divergence demand more precise fossil-based calibrations.Bayesian analysis ͉ molecular clock ͉ hominid ͉ fossil ͉ primate D etermining the age of the most recent common ancestor of humans and their closest African ape relatives has been the subject of scientific inquiry for over a century. This age is important for assessing the evolutionary rate of morphological and molecular changes in humans, assigning key fossils in hominoid phylogeny, and estimating when the common ancestor of all humans lived. The paleontological approach has been hampered by the paucity of fossils of some lineages. The first chimpanzee fossil, for example, was only just reported in 2005 (1). As recently as the mid-1960s (2), the African apes were considered to be distant relatives of the human lineage, but subsequent molecular phylogenetic analyses have shown that the chimpanzee and human are sister species and have led to a revision of the age of their divergence (3-13). Currently, the earliest unequivocal upright hominids at 4.2 millions of years ago (Ma) provide the minimum age for human-chimpanzee divergence (14), and some recently proposed early hominids dated between 5 and slightly more than 6 Ma are thought to provide an estimate close to the actual species divergence (15-19). However, a divergence time of 12.5 Ma for humans and chimpanzees has been entertained recently as well (20), and so the fossil record and its inte...