Pathogenesis by mycobacteria requires the exploitation of host-cell signaling pathways to enhance intracellular survival and persistence of the pathogen. Among patients with end-stage acquired immune-deficiency syndrome, disseminated infection with Mycobacterium avium, a member of the M. avium complex (MAC), is the most common bacterial infection. The virulence and intrinsic multidrug resistance of this pathogen has been attributed in part to its unique cell wall, which is a complex array of hydrocarbon chains containing the arabinogalactan-peptidoglycan mycolic acid core found in all mycobacteria, surrounded by a second electron-dense layer made up, in part, of serovar-specific glycopeptidolipids (GPLs) found only in MAC. Via cell-surface receptors, M. avium, an intra-macrophage (mφ) pathogen, can modulate various host signaling pathways such as the mitogen-activated protein kinase and nuclear factor κB pathways. The modulation of specific mφ signaling cascades can result in the regulation of pro- and anti-inflammatory cytokine production, and the process of phagolysosome fusion. The outcome of this M. avium-host mφ interaction could result in host disease or death of the invading pathogen. This review will focus on the immunomodulation aspects of M. avium pathogenesis as well as the role of GPLs as virulence factors.