The number of described primary immunodeficiencies (PIDs) and their classification have increased significantly in the last two decades. The clinical presentation of PIDs can be diverse and depends on the type of disease and the age of the child, which complicates the diagnostic procedure. The overall prevalence of all PIDs is significant and the patient's survival often depends on early recognition and treatment of the disorder. The International Union of Immunological Societies (IUIS) has classified these disorders into ten categories, comprising 500 inborn errors of immunity, based on the affected segment of the immune system. Various groups have developed models to distinguish patients with PIDs from those with other causes of recurrent infections. The models are mostly based on the assumption that children with PIDs are more likely to suffer from a serious infection. Most children who present recurrent infections, especially localized to one organ system, have an increased exposure, an allergy, or an anatomic problem rather than a defect in the immune response. However, many cases of PID remain undiagnosed or misdiagnosed and consequently inappropriately and unsuccessfully treated. The evaluation of PID should focus on the component of the immune system that is the most likely cause of the disease based on the initial evaluation. Many PIDs manifest in the neonatal period, and their diagnosis and optimal treatment are challenging. However, it is crucial to diagnose these disorders before severe infections and subsequent organ damage occur. According to all models, children who have recurrent infections require careful evaluation and management. Cure requires immune reconstitution, which can be achieved in several PID disorders through HSCT (Hematopoietic Stem Cells Transplantation), enzyme replacement, thymus transplantation, or gene therapy (GT). Newer therapies include small molecule inhibitors, biologic therapy, and the use of adoptive transfer of virus-specific T-cells. HSCT has been used as the therapy of choice for severe PIDs for more than 50 years, however it is associated with life-threatening complications. Patients with a thymic defect are candidates for thymic transplantation rather than HSCT, as conditioning and transplantation can lead to more severe immunodeficiency. Monoclonal antibodies have revolutionized targeted therapy and reduced the need for widespread use of immunosuppressive therapy. With the possibility of establishing a molecular diagnosis for patients with PIDs, there is growing interest in targeted therapies that can replace, augment, or modulate patients’ immunologic response. Small molecule inhibitors are targeted low molecular weight compounds that can easily enter cells and modulate other proteins, thereby significantly improving immune dysregulation. Virus-specific T-cells have been developed for use in the fight against viral infections in the pre- and post-transplant period. When it comes to a number of severe immunodeficiency diseases that only affect hematopoietic cell lineages, GT is both feasible and effective. The GE (Gene Editing) method has evolved from traditional GT, which includes targeted gene correction of a pathogenic variant while maintaining the use of the endogenous gene promoter and other regulatory elements. With the existing methodology, this technology cannot yet be widely used in clinical settings.