Worldwide, an estimated 12 million people are infected with spp. and an additional 350 million are at risk of infection. Leishmania are intracellular parasites that cause disease by suppressing macrophage microbicidal responses. Infection can remain asymptomatic or lead to a spectrum of diseases including cutaneous, mucocutaneous, and visceral leishmaniasis. Ultimately, the combination of both pathogen and host factors determines the outcome of infection. Leishmaniasis, as well as numerous other infectious diseases, exhibits sex-related differences that cannot be explained solely in terms of environmental exposure or healthcare access. Furthermore, transcriptomic evidence is revealing that biological sex is a variable impacting physiology, immune response, drug metabolism, and consequently, the progression of disease. Herein, we review the distribution, morbidity, and mortality among male and female leishmaniasis patients. Additionally, we discuss experimental findings and new avenues of research concerning sex-specific responses in cutaneous and visceral leishmaniasis. The limitations of current therapies and the emergence of drug-resistant parasites underscore the need for new treatments that could harness the host immune response. As such, understanding the mechanisms driving the differential immune response and disease outcome of males versus females is a necessary step in the development of safer and more effective treatments against leishmaniasis.