Although primary immunodeficiency diseases (PIDs) were first reported in India in the 1970s, those diagnoses were based predominantly on clinical presentations—very limited immunological analyses were performed. Therefore, the validity of many early reports of PIDs may be questionable. However, in the last 10–15 years, diagnoses of PIDs have been based on flow cytometric analysis and, in a few cases, by mutational analysis. In India, PIDs in adults are markedly underreported. We present data from two major centers where diagnosis of PID has been focused primarily in children. We highlight some of the limitations and challenges in the diagnosis and therapy of PID, and more recent efforts to establish PID Centers of Excellence and a national PID registry in India.