To reach the aim of safe and effective use of TNFα-TNFR manipulations in cancer therapy, we need to consider the possibility that one type of TNFα-TNFR-directed therapy is not suitable to all cancer types and to all cancer patients; moreover, a specific therapy mode that applies to one cancer type/subtype may be detrimental in another. This evidence concerns the gene TNFRSF1A and cancer.