Abstract In many species the mutation rate is higher in males than in females, a phenomenon denoted as male mutation bias. This is often observed in animals where males produce many more sperm than females produce eggs, and is thought to result from differences in the number of replication-associated mutations accumulated in each sex. Thus, studies of male mutation bias have the capacity to reveal information about the replication-dependent or replication-independent nature of different mutations. The availability of whole genome sequences for many species, as well as for multiple individuals within a species, has opened the door to studying factors, both sequence-specific and those acting on the genome globally, that affect differences in mutation rates between males and females. Here, we assess the advantages that genomic sequences provide for studies of male mutation bias and general mutation mechanisms, discuss major challenges left unresolved, and speculate about the direction of future studies.