The Mycobacterium tuberculosis genome was sequenced more than 15 years ago. It revealed a lot of interesting information, one of which was that 10% of the total coding capacity of the M. tuberculosis genome is dedicated to the PE/PPE family. There is a gradual expansion of these proteins from nonpathogenic to pathogenic mycobacteria, and there is increasing evidence that PE/PPE proteins play important roles in mycobacterial pathogenesis. In this review, we discuss PE/PPE proteins, their close functional association with the ESX clusters, their immunomodulatory functions, and their important roles in mycobacterial virulence. In addition, we have attempted to review and compile information available in the literature detailing the expression patterns of PE/PPE family members in different mycobacterial species and also during infection. Our attempt has been to provide a succinct overview of this interesting family.