• The reported substrates of Mtb ClpP1P2 proteolytic machinery were summarized. • The structure, function, and importance of Mtb ClpP1P2 proteolytic machinery as well as their modulators were fully discussed. • The structural types and binding modes of Mtb ClpP1P2 modulators were summarized. • Several pathways to modify the selective inhibitors and the existence of a potential selective allosteric site were concluded. • This review is helpful to researchers in field of Tuberculosis treatment. Caseinolytic protease P with its AAA1 chaperone, known as Mycobacterium tuberculosis (Mtb) ClpP1P2 proteolytic machinery, maintains protein homeostasis in Mtb cells and is essential for bacterial survival. It is regarded as an important biological target with the potential to address the increasingly serious issue of multidrug-resistant (MDR) TB. Over the past 10 years, many Mtb ClpP1P2-targeted modulators have been identified and characterized, some of which have shown potent anti-TB activity. In this review, we describe current understanding of the substrates, structure and function of Mtb ClpP1P2, classify the modulators of this important protein machine into several categories based on their binding subunits or pockets, and discuss their binding details; Such information provides insights for use in candidate drug research and development of TB treatments by targeting Mtb ClpP1P2 proteolytic machinery. [ABSTRACT FROM AUTHOR]