Mycobacterium tuberculosis (Mtb) remains an important human pathogen. The Mtb cell envelope is a critical bacterial structure that contributes to virulence and pathogenicity. Mycobacterial membrane protein large (MmpL) proteins export bulky, hydrophobic substrates that are essential for the unique structure of the cell envelope and directly support the ability of Mtb to infect and persist in the host. This review summarizes recent investigations that have enabled insight into the molecular mechanisms underlying MmpL substrate export and the role that these substrates play during Mtb infection.