Tuberculosis (TB) is one of the most devastating diseases primarily due to several decades of neglect, and presents a global health threat of escalating proportions. TB is the second leading infectious cause of mortality today behind only HIV/AIDS. The impetus for developing new structural classes of anti-tuberculosis drugs comes from the emergence of multi-drug resistant (MDR) strains to commonly used drugs, substantially longer durations of therapy that are needed as a result of resistance, and the resurgence of disease in immunocompromised patients. Recent years have witnessed emergence of many new structural classes of anti-TB agents, which have exhibited promising activities against drug-sensitive and drug-resistant strains of the causative organism Mycobacterium tuberculosis. These analogs ideally should decrease the overall duration of therapy with improved efficacy, and exhibit mechanisms of action different from those of existing drugs to counter the resistant strains of M. tuberculosis. This review provides a comprehensive literature compilation on advances in the new structural classes of anti-TB analogs reported during the past five years. Our discussion and observations are concentrated on chemotherapeutic potential of alphabetically listed twenty-seven new structural classes of anti-tuberculosis agents that include:- acetamides, 5-arylidene-2-thiohydantoins, benzoxazoles and benzothiazoles, benzoic acid hydrazones, benzoxazines, carbohydrates, chalcones, coumarins, deazapteridines, imidazoles, indoloquinazolinones, isothiosemicarbazones, mycobactins, 1,8- naphthyridines, phenazines, purines, pyridines, N-pyridinylsalicylamides, pyrimidines and thymidines, pyrroles, quinolines, quinoxalines, terpenes, thiadiazine thiones, thiolactomycines, toludines, and triazoles.