Globally, far more men than women have tuberculosis. Although the cause of this bias is uncertain, epidemiological factors have historically been considered the driving force. Here, we discuss evidence that biological differences between the sexes may also be important and can affect susceptibility to mycobacterial infection. We discuss the possible underlying mechanisms, with particular focus on how sex hormones modulate the immune responses necessary for resistance to tuberculosis. Studying these differences may provide valuable insight into the components that constitute an effective immune response to this deadly pathogen.