According to the WHO classification, Hodgkin's lymphoma (HL) is subdivided into a classical variant and a nodular lymphocyte predominant variant which are characterized by the presence of Hodgkin's and Reed-Sternberg (H-RS) cells or lymphocytic and histiocytic (L&H) cells, respectively. This article reviews genetic characteristics and transcriptional changes of H-RS and L&H cells, including recent knowledge about transforming mechanisms and signaling pathways that contribute to the antiapoptotic phenotype displayed by H-RS and L&H cells. We also discuss major cellular and molecular mediators contributing to the establishment and maintenance of a reactive background in HL-affected tissues. We believe that an in-depth understanding of the pathogenesis of HL will eventually lead to the development of novel biologically based therapeutic strategies in the near future.