Hand-foot skin reaction (HFSR) is a documented cutaneous adverse reaction to tyrosine kinase inhibitor (TKI) chemotherapy. Cutaneous toxicities such as HFSR can be debilitating and may result in serious complications; however, continued chemotherapy is desirable to optimize the patient's odds of survival and tumor remission. We present a case of a 66-year-old male, with a history of metastatic renal clear cell carcinoma, who was diagnosed with grade 3 HFSR triggered by axitinib, a tyrosine kinase inhibitor. Our patient was able to expeditiously resume chemotherapy after temporary cessation of axitinib with concurrent application of topical steroids and keratolytics. Expedient return to life-prolonging chemotherapy is of great importance for patients with advanced malignancies; therefore, accurate diagnosis and prompt identification of the offending medication are critical to the management of this entity. We aim to increase the awareness of tyrosine kinase inhibitor-induced HFSR and review the diagnosis and current guidelines for management.