Maturation of the antibody response is dependent on class-switch recombination (CSR) and somatic hypermutation (SHM), that modify the structure and the affinity of immunoglobulins, respectively. The cellular and molecular mechanisms involved in these processes have long remained obscure. During the last years, careful investigation of a cohort of rare patients with defective antibody responses have led to the identification of several genes that are critically involved in CSR and SHM. At the same time, recognition that defective maturation of antibody responses may result from different mechanisms, has been essential to better define prognosis and to tailor more appropriate and specific forms of treatment.