The substrate for the clinical variability of MF/SS patients is dependent on the integration of a series of heterogeneous molecular alterations involving the TCR–PLCG1, CCR4/7–MAPK, TNFR/NF-κB, and JAK/STAT signaling pathways, with proliferative and survival signals derived from the MF/SS microenvironment. The gene discussed is TNFRSF1A; the disease is mycosis fungoides.