Inflammation and cancer are two independent biological events that can play an interdependent role. The model of such interaction is represented by Hodgkin lymphoma (HL), where the microenvironment is dominated by an extensive mixed, potentially cellular inflammatory infiltrate that plays a decisive role in the pathobiology of HL. In this review we summarize updated information on the complex interactions between Hodgkin Reed-Sternberg (HRS) cells and their tissue microenvironment, highlighting the functional role of CD40/CD40L and interferon regulatory factor 4 (IRF4).