Recent progress resolving the phylogenetic relationships of the major lineages of mammals has had a broad impact in evolutionary biology, comparative genomics and the biomedical sciences. Novel insights into the timing and historical biogeography of early mammalian diversification have resulted from a new molecular tree for placental mammals coupled with dating approaches that relax the assumption of the molecular clock. We highlight the numerous applications to come from a well-resolved phylogeny and genomic prospecting in multiple lineages of mammals, from identifying regulatory elements in mammalian genomes to assessing the functional consequences of mutations in human disease loci and those driving adaptive evolution.