The 10 warning signs of primary immunodeficiency are being promoted as a screening tool for use by both the general public and physicians. A recent study, however, shows that except for family history, need for intravenous antibiotics and failure to thrive, the 10 warning signs are not a useful screen of primary immunodeficiency diseases (PIDs). Over the last few decades, there has been a revolution in our understanding of PID. The 10 warning signs do not take into account the fact that PIDs now include diseases that present with sporadic infections, autoimmunity, autoinflammation, and malignancy. This review focuses on the advances in our understanding of PID, the current limitations of the 10 warning signs, and recommendations to ensure that patients with PID are diagnosed in a timely fashion in the future.