Ubiquitin-specific proteases are deubiquitinating enzymes involved in the removal of ubiquitin from specific protein substrates resulting in protein salvage from proteasome degradation, regulation of protein localization or activation. DNA alteration and overexpression in different cancer types, as well as involvement in many cancer-associated pathways, make ubiquitin-specific proteases attractive for the cancer drug discovery purposes. Their proteolytic function associated to available structural biology data reinforce their potential for pharmacological interference. Here, we review this class of enzymes as cancer drug targets in terms of validation and druggability.