Interleukin (IL) -12 is a cytokine that has been extensively characterized for its immunoregulatory activities. IL-12 binds to a heterodimeric receptor composed of the beta1 and beta2 chains. In this review article, we discuss recent findings on the expression and function of IL-12 receptor (IL-12R) in malignant B cells frozen at various stages of differentiation and in their normal counterparts. These studies, together with others performed in Il12rb2 knockout mice, have established the concept that the IL-12Rbeta2 gene is a gatekeeper from cancer. We will delineate three paradigms reflecting the differential expression of IL-12Rbeta2 in different groups of malignant B cells and discuss the therapeutic perspectives stemming from these studies.