Mycobacterium avium is an environmental bacteria and a significant cause of disease in individuals with pre-existing lung conditions such as cystic fibrosis. It can also cause a disseminated infection in individuals who are immune-compromised with high infection rates observed in late stage AIDS patients. M. avium like other pathogenic mycobacteria have a complex cell wall and many of the cell wall components are known to play a significant role in bacterial pathogenesis. The outer leaflet of M. avium and other non-tuberculosis mycobacteria (NTMs) contain glycopeptidolipids (GPLs), a unique, surface-exposed, antigenic molecule that is able to interact with host pattern recognition receptors including the Toll-like receptor 2 and mannose receptor. These molecules have also been implicated in eliciting immune responses, transcriptional modification, phagosome trafficking, sliding motility, and biofilm formation. As GPLs are surface-exposed and early engagers of host cell receptors, they are predicted to play an important role in the host response to a mycobacterial infection. In this review we will discuss the composition, biosynthesis and biological function of this diverse surface molecule and identify gaps in our understanding of GPLs as potential virulence factors for M. avium and other NTMs.