While the exact role of HsClpP in tumorigenesis is not clear, certain types of cancers are highly dependent on the protease for cell proliferation and metastasis. In light of these observations, recent research has focused on the discovery and characterization of small organic molecules that can target and modulate HsClpP activity. These include compounds that inhibit HsClpP’s proteolytic activity via covalent modification of its catalytic Ser residue as well as those that activate and dysregulate HsClpP by displacing HsClpX to negate its regulatory role. Importantly, several of these compounds have been shown to induce HsClpP-dependent apoptotic cell death in a variety of cancerous cells. This review provides an overview of these research efforts and highlights the various types of small molecule modulators of HsClpP activity with respect to their potential use as cancer therapeutics.