Tuberculosis (TB) continues to remain at the forefront of the infectious disease burden globally, albeit with some aberrations during the COVID-19 pandemic. Among many factors, the emergence of drug resistance or antimicrobial resistance (AMR) has necessitated a renewed focus on developing novel and repurposed drugs against TB. Host-directed therapy (HDT) has emerged as an attractive alternative and a complementary strategy to the conventional antibiotic-based therapy of tuberculosis since HDT enjoys the advantage of disarming the pathogen of its ability to develop drug resistance. Considering the imminent threat of AMR across the spectrum of bacterial pathogens, HDT promises to overcome the drug shortage against superbugs. While all these make HDT a very attractive strategy, identifying the right set of host targets to develop HDT remains a challenge, despite remarkable development in the field over the past decade. In this review, we examine the host mechanisms, that either inadvertently or through targeted perturbation by the pathogen, help TB pathogenesis, and we discuss the latest developments in the targeting of some of the key pathways to achieve newer TB therapeutics.