Spontaneous models of lupus were recognized four decades ago beginning in the early 1960s with the NZB/NZW F1 (NZB/W F1) mouse, an F1 hybrid between the New Zealand Black (NZB) and New Zealand White (NZW) mice. Although the parental strains display limited autoimmunity, the NZB/W F1 develops severe lupuslike features similar to that of human lupus patients. Here, we will address the genetic characteristics of the model and discuss its main characteristics such as the presence of serum antinuclear autoantibodies (ANA) including anti-dsDNA, mild vasculitis, and the development of immune complex-mediated glomerulonephritis. Similar to human lupus, the disease develops primarily in female mice after six months of age, with a lesser percentage and severity in male mice. The relation of this phenomenon will be examined in the context of estrogen levels. The participation of both innate and adaptive immunity will be addressed as well as the contribution of both T and B cells in the development of the clinical aspects of the disease. We will focus on the use of the model as a valuable tool for elucidating the pathogenic mechanisms of the disease, as well as its use as preclinical testing of therapeutic for human use.