A major virulence factor of pathogenic mycobacteria is their ability to parasitize the host's scavenger cells and more particularly macrophages. The present overview discusses the known cellular and molecular mechanisms of intracellular survival of Mtb and other pathogenic mycobacteria within different intracellular niches, i.e. the macrophage in which they replicate and the granuloma in which they persist in a non-replicating state. After phagocytic uptake by macrophages, mycobacteria reside in phagosomes which they prevent from maturing and, as a result, from fusing with acidic and hydrolase-rich lysosomes. Two major points are highlighted: (i) the requirement for a close apposition between the phagosome membrane and the mycobacterial surface all around, and (ii) the ability for mycobacteria targeted to phagolysosomes to avoid degradation and to be rescued from this cytolytic environment to again reside in non-maturing phagosomes with a closely apposed membrane in which they can replicate. Concerning Mtb in granulomatous lesions, this review discusses the occurence of mycobacteria in lipid-rich foamy macrophages in which they persist in a non-replicating state. This overview highlights the major contribution of host cholesterol and/or fatty acids (triacylglycerol) in both prevention of phagosome maturation and persistence in granulomatous lesions.