Approximately one-third of the world's population is infected with Mycobacterium tuberculosis, and the World Health Organization estimates 1.6 million deaths were caused by M. tuberculosis in 2005. The enormous worldwide burden of disease underscores the proficiency by which M. tuberculosis is able to evade eradication by the host, subverting innate and adaptive defences. At the cellular level, mycobacteria are able to modulate macrophage defences by altering phagosome maturation. This review focuses on the bacterial proteins and lipids that are important in establishing the mycobacterial replicative niche. While there is a detailed molecular description of the vacuole and an increasing number of bacterial effectors have been implicated in creating this compartment, exactly how they intersect host cell processes remains ill-defined. However, the emerging picture is that an array of lipid and protein effectors collaborate to create and maintain the mycobacterial phagosome.