Till date we believed that multidrug-resistant and extensively drug resistant were our deadliest foes when dealing with tuberculosis. However, conditions commonly encountered in daily practice such as diabetes, liver, renal, psychiatric disorders, and pregnancy tend to frequently overlap with tuberculosis. These multimorbid conditions prove to be equally challenging for an average medical practitioner. Inappropriate prescriptions in the above situations prove to be a significant impediment to the overall control of tuberculosis in the community at large. The advent of solid organ transplantation and aggressive use of immunosuppressive medication for malignancies and chronic inflammatory disorders has added a new dimension to the already preexisting challenges faced by practicing clinicians, particularly in the context of treating tuberculosis in the immunocompromised and drug-drug interactions. This is another area which needs special attention. Pediatric multidrug resistant tuberculosis is a growing menace and needs to be controlled before it becomes an insurmountable problem. In addition, the emerging epidemics of metabolic syndrome, substance abuse, and drug dependence have only compounded the problem. Tuberculosis in the above populations, particularly if drug resistant can be one of the worst nightmares for the treating clinician. This article tries to highlight these prevalent issues and offers practical and evidence-based solutions to help clinicians in their endeavor to achieve a tuberculosis free world.