Surface‐expressed BCR mediates the proliferation and expansion of antigen‐specific B lymphocytes during a humoral immune response. Although several studies extensively characterize BCR proliferative signaling, the mechanisms linking these pathways to the cell cycle remain elusive. Using knockout mice, we show that c‐Rel, a proto‐oncogenic member of the NF‐κB transcription factor family, is essential to BCR‐mediated proliferation and cell cycle progression. Splenic B cells obtained from gene‐targeted c‐Rel knockout mice display a defective proliferation response to antigen receptor cross‐linking, resulting in G₁ arrest. At the molecular level, we see that BCR stimulation of resting c‐Rel^–/– B cells fails to induce proper cyclin D3 and cyclin E expression, thereby negatively impacting G₁ phase cyclin‐dependent kinase (CDK) activity. c‐Rel‐deficient B cells also exhibit incomplete phosphorylation of the Retinoblastoma protein (pRb) and poor expression of E2Fs, thus impeding the G₁ to S phase transition. Down‐regulation of the pRb‐related p130 protein during the G₀ to G₁ transition and removal of the CDK inhibitor p27^KIP1 in late G₁ parallel that of wild‐type cells, suggesting that Rel‐deficient B cells can exit the G₀ resting state and enter G₁ phase normally. Finally, we demonstrate that restoration of proliferation can be achieved partially upon reintroduction of cyclin E using a protein transduction method to reconstitute primary B cells. Collectively, these studies emphasize the importance of c‐Rel in lymphocyte proliferation and oncogenesis, and highlight a requirement for c‐Rel in establishing an effective humoral immune response.