Disclosed are methods of treating diseases or disorders associated with the expression of Ubiquitin Specific Peptidase 22 (USP22). The disclosed methods may be utilized to treat diseases or disorders associated with cell proliferation, including cancer. Also disclosed are inhibitors of USP22 that specifically inhibit the EC:3.4.19.12 activity, or the thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal glycine of ubiquitin. The disclosed compounds may also be used in pharmaceutical compositions and methods for treatment of cell proliferative diseases or disorders associated with USP22 activity.