The human immune system is critical for maintaining health and providing protection from infectious diseases and cancer. Major advances in our understanding of the immune system have largely emerged from studies using animal models such as mice. However, this mouse-centric research has also limited our ability to comprehend the human immune system and how it changes with age and disease state. The fact that we have yet to define what constitutes a normal human immune system has hampered our ability to diagnose, treat, and prevent many human diseases. Immunoprofiling that measures the frequency of human immune cells based upon their functional biomarkers is critical for immunotherapy. With major advances in flow cytometry, mass cytometry, and imaging technology it is now possible to rapidly characterize many types of immune cells for immunotherapy and for monitoring disease. In this article, we discuss recent progress in immunoprofiling of the human immune system and how this system changes with age, chronic diseases, and autoimmunity. We also discuss this in the historical context as it relates to the emergence of human immunology. New knowledge generated by immunoprofiling studies will allow better understanding and monitoring of immune cells and their application in clinical medicine.