() is one of the most successful human pathogens, causing a severe and widespread infectious disease. The frequent emergence of multidrug-resistant (MDR) strains has exacerbated this public health crisis, particularly in underdeveloped regions. employs a sophisticated array of virulence factors to subvert host immune responses, both innate and adaptive. It utilizes the early secretory antigenic target (ESAT6) secretion system 1 (ESX-1) type VII secretion system (T7SS) and cell wall lipids to disrupt phagosomal integrity, inhibiting phagosome maturation, and fusion with lysosomes. Although host cells activate mechanisms such as ubiquitin (Ub), Ub-ligase, and cyclic GMP-AMP synthase-stimulator of interferon genes 1 (CGAS-STING1)-mediated autophagy to inhibit survival within macrophages, the pathogen counteracts these defenses with its own virulence factors, thereby inhibiting autophagy and dampening host-directed responses. T7SSs are critical for transporting proteins across the complex mycobacterial cell envelope, performing essential functions, including metabolite uptake, immune evasion, and conjugation. T7SS substrates fall into two main families: ESAT-6 system proteins, which are found in both Firmicutes and Actinobacteria, and proline-glutamic acid (PE) and proline-proline-glutamic acid (PPE) proteins, which are unique to mycobacteria. Recent studies have highlighted the significance of T7SSs in mycobacterial growth, virulence, and pathogenesis. Understanding the mechanisms governing T7SSs could pave the way for novel therapeutic strategies to combat mycobacterial diseases, including tuberculosis (TB).