“Infection resisters” are broadly defined as individuals who despite significant exposure to Mycobacterium tuberculosis remain persistently unreactive to conventional detection assays, suggesting that they remain uninfected or rapidly clear their infection early on following exposure. In this review, we highlight recent studies that point to underlying host immune mechanisms that could mediate this natural resistance. We also illustrate some additional avenues that are likely to be differently modulated in resisters and possess the potential to be targeted, ranging from early mycobacterial sensing leading up to subsequent killing. Emerging research in this area can be harnessed to provide valuable insights into the development of novel therapeutic and vaccine strategies against M. tuberculosis.