Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease characterized by autoantibody production, complement activation, and immune complex deposition. It predominantly affects young and middle-aged women. While improvements in the diagnosis and treatment of SLE have altered prognosis, morbidity and mortality rates remain higher than the general population. In addition to renal injury, cardiovascular disease, and infection, malignancy is known to be a significant cause of death in this population. There is increasing evidence to suggest that patients with SLE have a slightly higher overall risk of malignancy. The risk of malignancy in SLE is of considerable interest because the immune and genetic pathways underlying the pathogenesis of SLE and the immunosuppressant drugs (ISDs) used in its management may mediate this altered risk. Our current understanding of these and other risk factors and the implications for treating SLE and screening for malignancy is still evolving. This review summarizes the association between SLE and malignancy. The first section discusses the risk of overall and site-specific malignancies in both adult- and pediatric-onset SLE. Next, we evaluate the risk factors and possible mechanisms underlying the link between malignancy and SLE, including the use of ISDs, presence of certain SLE-related autoantibodies, chronic immune dysregulation, environmental factors, and shared genetic susceptibility. Finally, we review guidelines regarding cancer screening and vaccination for human papilloma virus.