Numerous examples indicate that mammalian development can be entirely normal in the absence of the immune system; indeed, prior to birth, individuals with even very severe immunodeficiencies are developmentally unaffected. Perhaps it is not surprising, therefore, that more than 95 different primary immunodeficiency syndromes have been identified, encompassing defects in lymphocytes, phagocytes, and complement proteins. Indeed, within the past several years, more than 70 separate genes have been identified whose mutations cause immunodeficiency. These discoveries have been made both by using candidate gene approaches and by positional cloning. In some cases, the generation of gene-targeted mice preceded the identification of human mutations, whereas in other cases, the reverse was true. Therapy for these disorders, ranging from replacement therapy to bone marrow transplantation and gene therapy, has also moved at a rapid pace. This field therefore provides outstanding examples of the power of molecular medicine, with tremendous opportunities for interplay between basic and clinical science. Many of the processes that govern development of lymphoid and hematopoietic cells are now understood in some detail. We know that the growth and development of hematopoietic precursors, which develop in the fetal liver and bone marrow, are dependent upon a panoply of cytokines. In addition, lymphocytes require appropriate signals from antigen receptors to mature properly (Figure (Figure1).1). Additionally, other receptors and counter-receptors on lymphoid and antigen-presenting cells are critical for initiating immune responses (Figure (Figure2).2). We will provide examples in which mutations affect each of these steps and consequently result in immunodeficiency (Table (Table1).1). Several excellent reviews provide comprehensive discussion of the genetic basis of primary immunodeficiencies (1, 2). Our goal is not to summarize this field in its entirety; rather, a major focus of this review will be the role of cytokines and their receptors in the pathogenesis of primary immunodeficiencies. Additionally, the identification of new genes associated with immunodeficiency disorders, insights from patient-derived mutations, the heterogeneity of clinical presentations, the significance of revertants, and advances in gene therapy will be highlighted. To an extent, the areas emphasized are also a reflection of our interests, but in general the lessons are applicable to most of the diseases encompassed by primary immunodeficiencies. Figure 1 Schematic representation of lymphoid development and genetic lesions leading to immunodeficiency. Figure 2 The development of lymphoid cells is dependent upon the expression and signaling by cytokine receptors, antigen receptors, and adhesion/accessory molecules. Mutations of many different genes can interfere with proper lymphoid development and function ... Table 1 Defects leading to primary immune deficiency