Knowledge of the rate of point mutation is of fundamental importance, because mutations are a vital source of genetic novelty and a significant cause of human diseases. Currently, mutation rate is thought to vary many fold among genes within a genome and among lineages in mammals. We have conducted a computational analysis of 5,669 genes (17,208 sequences) from species representing major groups of placental mammals to characterize the extent of mutation rate differences among genes in a genome and among diverse mammalian lineages. We find that mutation rate is approximately constant per year and largely similar among genes. Similarity of mutation rates among lineages with vastly different generation lengths and physiological attributes points to a much greater contribution of replication-independent mutational processes to the overall mutation rate. Our results suggest that the average mammalian genome mutation rate is 2.2 109 per base pair per year, which provides further opportunities for estimating species and population divergence times by using molecular clocks.