The rapid expansion in the past two decades in the understanding of the molecular basis of a large variety of novel congenital immunodeficiencies has provided valuable information on the signal transduction general mechanisms, that goes far beyond the comprehension of the individual disease. In most cases, the altered molecules are exclusively expressed in haematopoietic cells, while in other cases they are not restricted to a certain cell type. This leads to more complex clinical phenotypes, which contribute to unravel previously unappreciated non-haematopoietic functions of signaling proteins and the mechanism of coordination and integration of several pathways. Moreover, this knowledge will help define potential new therapeutic strategies through novel molecular targets, drive stem cell development into the desired differentiation path and ameliorate our comprehension of tissue engineering. This review focuses on the multiple roles in haematopoietic and non-haematopoietic receptors of the gamma signaling element with a special attention paid to the participation of gamma to growth hormone receptor signaling, confirming the presence of an interplay between endocrine and immune system.