Tuberculosis (TB) is a world-leading infectious disease caused by Mycobacterium tuberculosis (Mtb). The current treatment lasts 6 months and has contributed to the development of multidrug resistant (MDR) strains that nowadays cause almost half a million deaths around the globe. Forty years of research have rendered only 1 new drug to treat the new MDR strains. In the current review we present emerging trends to treat TB particularly focused on natural and synthetic peptides. The ability of some of these peptides to display multifunctional roles in TB treatment, particularly immune system modulation through autophagy and direct antimicrobial activity against Mtb, may present advantages to control the impact of this disease. We review the mechanisms of action relevant in the development of multifunctional peptides that may lead to evaluate new ways to treat TB, a disease that has accompanied human society for centuries