Severe combined immunodeficiencies (SCID) are a heterogeneous group of rare, genetic diseases resulting in profoundly impaired adaptive immune responses. SCID is fatal without treatment due to the development of severe, recurrent infections. The establishment of universal newborn screening (NBS) for SCID and optimization of hematopoietic stem cell transplantation (HSCT), the curative treatment for SCID, have led to improved detection and early treatment of patients with SCID, which has significantly reduced morbidity and mortality. Despite these diagnostic and therapeutic tools, significant challenges remain such as normalizing thresholds for newborn screening, preventing peri-transplant infection, choosing conditioning regimens that balance toxicity with immunosuppression, post-transplant monitoring, and addressing the quality-of-life and social needs of SCID patients and their families. Advances in molecular biology have led to the development of novel genetic therapies for particular subtypes of SCID, notably adenosine deaminase (ADA) deficiency, which provide promising ways to address many of these challenges. Future guidelines will need to incorporate a mutation-specific approach to optimize HSCT parameters and gene therapy recommendations so personalized medical care to SCID patients can be provided.