The cancer incidence in inborn errors of immunity (IEI), a group of genetic disorders that lead to changes in the immune system’s development/function, is estimated to be 40 times higher than in the general population. In addition to susceptibility to lymphoproliferation/malignancies, the risks of infectious, autoimmune/inflammatory, and allergic diseases are also increased in IEI. This chapter explores the mechanisms linking IEI and cancer, highlighting the need for new approaches to enhance patient care and achieve better long-term outcomes based on clinical experience at IEI. Cancer develops through genetic/epigenetic changes and environmental/exposome factors impairing normal cellular functions. The failure of immune surveillance and ongoing inflammation are key factors in carcinogenesis. Chronic inflammation due to persistent infections and inflammatory/autoimmune diseases also increases cancer susceptibility. Cancer/lymphoproliferation risk is high in patients with defective DNA repair and centromeric instability. Dysregulation of immune pathways through the activation of oncogenes and tumor suppressor gene inhibition is another carcinogenesis mechanisms in IEI. Future research should focus on identifying genetic/epigenetic and exposome factors driving carcinogenesis in IEI since understanding the role of immune dysregulation in tumor development has the potential to improve early diagnosis, customize treatments and implementing preventive strategies for cancer. Recent advances in molecularly targeted therapies, such as immune checkpoint inhibitors and monoclonal antibodies like rituximab, are promising improved cancer control in immunodeficient patients. Hematopoietic stem cell transplantation and gene therapy also offer a potential approach to managing malignancies in IEI. A multidisciplinary approach involving immunologists, hematologists, and geneticists is critical for optimizing patient outcomes through individualized therapies, family screening, and genetic counseling.