In the canonical NF-κB signaling pathway, stimulation of various receptors, which complex with TNF receptor–associated factors (TRAFs) and the receptor interacting protein (RIP), leads to activation of the IKK complex, targeting the NF-κB inhibitors IκBα and IκB for ubiquitination and proteasomal degradation. As a consequence, the NF-κB transcription factors translocate into the nucleus, where they activate multiple genes. TNFAIP3 and CYLD are further negative regulators of NF-κB signaling. In the alternative NF-κB pathway, activation of receptors such as CD40 and TACI causes stimulation of the kinase NIK (MAP3K14), which then activates an IKKα complex. NIK activity is negatively regulated by TRAF3. Activated IKKα processes p100 to p52, which translocates as p52/RELB heterodimers into the nucleus. HRS cells have constitutive activity of both NF-κB pathways. Activation of CD40, RANK, BCMA, and TACI through ligands expressed on lymphoma-infiltrating cells likely contributes to this activity. Numerous genetic lesions and signaling through the EBV-encoded latent membrane protein 1 in EBV-positive cases of HL play important roles in the deregulated NF-κB activity. The JAK/STAT pathway is the main signaling pathway for cytokines. In HRS cells, STAT3, -5, and -6 are constitutively active. In addition to activation of cytokine receptors, such as the IL-13 receptor and the IL-21 receptor, activation of this pathway is mediated by genomic gains or translocations of the JAK2 gene and frequent inactivating mutations of the SOCS1 gene. The frequency of genetic lesions and viral infections affecting NF-κB or STAT activity in HRS cells is indicated as percentages. Adapted with permission from Nature Reviews Cancer (2).