Patients diagnosed with metastatic cancer often receive a very poor prognosis with decreased survival expectancy compared to patients with localized cancer. While targeted therapies designed to slow aggressive cancers before metastasis are promising, there is still much work needed in understanding the mechanisms that promote tumor development and metastasis. To advance this foundational knowledge, important genes and proteins must be extensively studied to determine how they function in the context of cancer. One understudied protein, especially after considering how cancer cells acquire a dependence on it, is the mitochondrial sirtuin 5 (SIRT5), which has received increasingly more attention and study as a tumor promoting protein in aggressive cancers. SIRT5 is known to remove negatively charged acyl groups from lysine residues, and is widely considered a key regulator of metabolism as the majority of its protein substrates are important metabolic enzymes in glycolysis, the TCA cycle, and glutamine metabolism. SIRT5 is consistently and significantly upregulated in these types of cancer, including triple-negative breast cancer (TNBC) and colorectal cancer (CRC). Targeting SIRT5 in various models of cancer has shown to be promising in reducing cancer cell proliferation, tumor growth, and cancer metastasis. However, the understanding SIRT5 dependency in cancers and the effects of targeting it are still limited.