Small ubiquitin-like modifiers (SUMO) conjugation to cellular proteins is a reversible posttranslational modification that mediates the protein's function, subcellular localization, and/or expression. The SUMO proteases (SENP) deconjugate modified proteins and thus are critical for maintaining the level of SUMOylated and un-SUMOylated substrates required for normal physiology. Altered expression of SENPs is observed in several carcinomas. This review focuses on how the change in SENP levels disturbs SUMO homeostasis and contributes to cancer development and progression. We reported that one member of the SENP family, SENP1 can transform normal prostate epithelia to a dysplasic state and directly modulate several oncogenic pathways in prostate cells, including AR, c-Jun, and Cyclin D1. Assessment of tissue from human prostate cancer patients indicates elevated mRNA levels of SENP1 and the SUMO2/3 deconjugating enzyme, SENP3. The induction of SENP3 in cancer cells initiates the angiogenic pathway; specifically SENP3 regulates the transcriptional activity of hypoxia-inducible factor 1α (HIF1α) via deSUMOylation of the co-regulatory protein p300. Unlike prostate cancer, enhanced SUMOylation is favored with onset of breast cancer and correlated with the reduced SENP6 mRNA levels found in several breast cancer tissue arrays. Preventing enhanced SUMO conjugation of cellular substrates in breast cancer cells reduces tumorigenesis. Hence, distortion of SUMO equilibrium contributes to both the initiation and progression of cancer, specifically in prostate and breast cancers. The deSUMOylation machinery may be key to restoring balance to the SUMO system and hence serve as ideal targets for therapeutic agents.