To characterize Reed-Sternberg (R-S) cells by proteomic analysis in order to gain insight into the molecular pathways that control their growth and thereby to discern potential molecular interventions in Hodgkin’s disease. Ten cases of the nodular sclerosing (NS) subtype and 4 cases of the lymphocyte-predominant (LP) subtype were studied. Immunohistochemical procedures were performed to detect the following antigens: CD20, CD30, c-kit, platelet-derived growth factor receptor (PDGFR)-α, cathepsin D, angiotensin-converting enzyme (ACE), angiotensin II type 1 (AT1) receptor, phosphorylated c-Jun N-terminal kinase (p-JNK), c-Jun, Ki-67, the latency-associated peptide (LAP) of transforming growth factor-beta 1 (TGF-β1), and the TGF-β receptor (TGF-βRII). Immunoreactivities were scored from 0 to 3+ positivity using bright-field microscopy. The tyrosine kinase signal transducer, PDGFR-α, the AT1 receptor transactivator, the p-JNK downstream effector, Ki-67, and proapoptotic TGF-β1 (LAP) were detected in R-S cells of the NS and LP subtypes; companion dendritic cells expressed cathepsin D and ACE. Intranuclear c-Jun was present in the NS subtype and stronger immunoreactivity for TGF-βRII was evident in the LP subtype. These data corroborate observations in the literature, characterizing R-S cells as possessing molecular pathways that incorporate PDGFR-α signaling and angiotensin transactivation with a potential for growth inhibition through activation of TGF-β1 and upregulation of its receptor. Specific therapies to target R-S cells in Hodgkin’s disease might include STI571, an AT1 receptor inhibitor, and retinoids.