Mycobacteria, such as the major human pathogen Mycobacterium tuberculosis, have a highly unusual and characteristic diderm cell envelope that protects them against harmful conditions. Protein secretion across this hydrophobic barrier requires specialized secretion systems. Recently, a type VII secretion (T7S) pathway has been identified that fulfills this function. Pathogenic mycobacteria have up to five different T7S systems, some of which play a crucial role in virulence. The interactions between secreted substrates and host molecules are only starting to become clear and will help in furthering our understanding of the persistence of these enigmatic pathogens. In this review, we discuss current knowledge on the role of T7S systems in mycobacterial virulence. © 2012 Elsevier Ltd.