Bladder cancer incidence is drastically higher in males than females across geographical, racial, and socioeconomic strata. Despite potential differences in tumor biology, however, male and female bladder cancer patients are still clinically managed in highly similar ways. While sex hormones and sex chromosomes have been shown to promote observed sex differences, a more complex story lies beneath these evident sex-biasing factors than previously appreciated. Advances in genomic technology have spurred numerous preclinical studies characterizing elusive sex-biasing factors such as epigenetics, X chromosome inactivation escape genes, single nucleotide polymorphism, transcription regulation, metabolism, immunity, and many more. Sex-biasing effects, if properly understood, can be leveraged by future efforts in precision medicine based on a patient's biological sex. In this review, we will highlight key findings from the last half century that demystify the intricate ways in which sex-specific biology contribute to differences in pathogenesis as well as discuss future research directions.