Overexpression of HECT-type E3 ubiquitin ligase SMURF1 is correlated with poor prognosis in patients with various cancers, such as glioblastoma, colon cancer, and clear cell renal cell carcinoma. SMURF1 acts as a tumor promoter by ubiquitination modification and/or degradation of tumor-suppressing proteins. Combined treatment of Smurf1 knockdown with rapamycin showed collaborative antitumor effects in mice. This review described the role of HECT, WW, and C2 domains in regulating SMURF1 substrate selection. We summarized up to date SMURF1 substrates regulating different type cell signaling, thus, accelerating tumor progression, invasion, and metastasis. Furthermore, the downregulation of SMURF1 expression, inhibition of its E3 activity and regulation of its specificity to substrates prevent tumor progression. The potential application of SMURF1 regulators, specifically, wisely choose certain drugs by blocking SMURF1 selectivity in tumor suppressors, to develop novel anticancer treatments.