The human immune system is one of the complex systems of the body, which works against both external and internal invasion. It has two parts: the innate and the acquired immune systems. We have been born with the innate system which gives a quick response for the invading pathogen non-specifically. To deal with the typical environmental antigens, immune system adapts to changes. The acquired (or adaptive) component develops over time and produces antibodies that “remember” invaders to fight them if they return. Failure of it could be due to genetic defect (weak natural immunity), inability to adapt to the change, hyper-responsiveness, or inability to distinguish self from foreign, leading to various diseases and disorders. Various genetic defects of the immune system are at the core of Primary Immune disorders (PIDs), while overactivity is responsible for allergic diseases. Autoimmune diseases are mostly due to malfunction of the adaptive immune system, while in Systemic Autoinflammatory Disorders (SAIDs), the innate immune system is affected. Advancements in technology and genetics have improved our understanding of the pathogenesis, diagnosis, and management of these diseases.