Currently, the mainstay of treatment for advanced and metastatic hormone receptor positive (HR+), Human Epidermal Receptor -2 (HER-2) negative breast cancer includes the combination of CDK4/6 inhibitors (ribociclib, palbociclib, and abemaciclib) with endocrine therapy. However, interpatient variability has been associated with increased toxicity or questionable therapeutic responses. Indeed, several factors such as concomitant medications and pharmacogenetics may significantly affect the absorption, distribution, metabolism and elimination of CDK4/6 inhibitors, resulting in subtherapeutic or toxic plasma levels. Traditionally, depressive symptoms have been highly associated with cancer patients, and thus antidepressant therapy (typically SSRIs or SNRIs) is frequently co-initiated early in the course of cancer treatment. This brief review aims to compile and present existing data regarding the safety profiles as well as drug-drug interactions that may result from the co-administration of CDK4/6 inhibitors with SSRIs/SNRIs. Increased awareness by medical oncologists warrants a safer and more effective clinical use of CDK4/6 inhibitors.