Primary immunodeficiencies (PIDs) result from defects in genes affecting the immune and other systems in many and varied ways, which collectively predisposes to frequent and severe infections, autoimmune disorders, and cancers. Until recently, treatments of PIDs have been largely supportive, with the exception of bone marrow transplantation. In the last decade, life expectancy of PID patients has improved dramatically, as a result of earlier diagnosis, better prevention, and treatment of infections and autoimmune complications, as well as advancement in therapeutic options. Life span extension, however, has been associated with increasing risk of cancer development. The overall risk for developing cancers in PID patients is 4–25%, with lymphomas representing up to 60% of cancers. Defective immunosurveillance mechanisms and infection with oncogenic viruses have significant contributory roles in many cases. In this chapter, we review our understanding of the spectrum and pathogenesis of cancers in the context of immunodeficiency syndromes, with emphasis on the epidemiologic data, clinical patterns, and potential importance of cancer screening for patients with specific PIDs.