The ability to pre-select offspring sex via separation of X- and Y-bearing sperm would have profound ramifications for the animal husbandry industry. No fully satisfactory method is as yet available for any species, although flow sorting is commercially viable for cattle. The discovery of antigens that distinguish X- and Y-bearing sperm, i.e. offspring sex-specific antigens (OSSAs), would allow for batched immunological separation of sperm and thus enable a safer, more widely applicable and high-throughput means of sperm sorting. This review addresses the basic processes of spermatogenesis that have complicated the search for OSSAs, in particular the syncytial development of male germ cells, and the transcriptional dynamics of the sex chromosomes during and after meiosis. We survey the various approaches taken to discover OSSA and propose that a whole-genome transcriptional approach to the problem is the most promising avenue for future research in the field.