Attempts to define the role of USF in stress responses and cancer development are complicated by an essential role for USF in differentiation, which results in embryonic lethality of mice that carry USF1/USF2 double knockout mutations or USF dominant negative transgenes, and by the ability of homodimers of either USF1 or USF2 to partially compensate for loss of the other’s activity in single gene knockout animals [29,30]. The gene discussed is USF2; the disease is cancer.