During the second half of the 20th century, organ transplantation saved thousands of lives. This, unfortunately, also led to unforeseen consequences that need to be addressed to help extend the lives of patients who require these life-saving procedures. Secondary malignancies have been recognized as a potential consequence for decades. One of these malignancies, squamous cell carcinoma of the skin, not only appears more frequently in organ transplant recipients than the general population, but also is more aggressive in organ transplant recipients. It also shows a high propensity to nodal spread and metastasis in transplant patients. Unfortunately, there are no clear guidelines for a chemotherapy in this population, who have an increased need for alternative therapies to surgery given the high recurrence and metastasis rate. In this review, we attempt to describe the characteristics of squamous cell carcinoma of the skin in transplant recipients and discuss what chemotherapeutic options can be used to treat this aggressive malignancy.