Human immunodeficiency virus (HIV) is a causative agent of AIDS while Mycobacterium tuberculosis causes human tuberculosis, independently. HIV and M. tuberculosis co-infection is an intriguing immunopathological phenomenon. The effect is not simply an additive but far more than that. This review gives an account of how various host and pathogen specific factors interplay to make this co-infection one of the worst co-infection, rightly named as medical “double jeopardy”. We have attempted to recount some of the immune mechanisms how both these pathogens disturb the balance of host immune system resulting into defects in the host phagocytic response, leading to apoptosis and chemokine dysregulation. The HIV provides protected shelter to the M. tuberculosis and M. tuberculosis provides conducive atmosphere through the interplay of various chemokines. We also touch upon the treatment associated complications like Immune reconstitution inflammatory syndrome (IRIS) these patients face.