Management of tuberculosis, already a global health emergency, is becoming increasingly challenging with extensive misuse of second line drugs and their inaccessibility to eighty percent of the eligible patients. Rising statistics of antimicrobial resistance underscores the need for a set of completely new and more effective class of compounds with novel mechanisms of action that can be administered in combination to replace and shorten the present intensive six months regimen. In this review, we stress on the importance and the successes of phenotypic screening for discovery of anti-mycobacterial compound and discuss the importance of performing secondary screens and counter screens to get early estimate on compound's potentials for a successful development. We also highlight the recent advances and the related caveats in the assays that have been developed and discuss new screening modalities that can be incorporated during hit-selection to gain a quick insight into the mechanism of action, thus enabling quicker decisions in a hit triage.