Epidemiologic data have demonstrated significant increases of various cancers in people with obesity and diabetes. Recently, concern has emerged that antihyperglycemic medications may also be associated with an increased prevalence of multiple cancers; however, available data are limited and conflicting. The American Association of Clinical Endocrinologists (AACE) convened a conference to review factors associated with cancer development in people with obesity and diabetes and to discuss the possible cancer risk of antihyperglycemic medications. Increased body mass index is associated with an increased risk of multiple cancers based on observational epidemiological data, and is closely associated with increased levels of endogenous insulin, insulin-like growth factors, inflammatory cytokines, and other factors that can have downstream pro-cancer growth effects. The role of hyperglycemia in cancer development is less clear, but an association cannot be ruled out, as current observational data additionally suggest an increased cancer risk in people with diabees. There is currently insufficient evidence that antihyperglycemic medications may be definitively associated with an increased cancer risk owing to a lack of data from large-scale randomized study designs. Similarly, there is also insufficient evidence showing a positive impact of these medications on cancer development. Clinicians can continue to confidently prescribe all FDA-approved antihyperglycemic medications for the management of hyperglycemia according to established practice guidelines. In patients who have an elevated cancer risk or positive family history of cancer, the cautious selection of antihyperglycemic medications is both prudent and warranted. The AACE additionally advocates for the improved treatment and management of obesity, early cancer screening in patients at increased risk, increased research collaboration, and improved study designs to address outstanding concerns surrounding the diabetes-cancer relationship.