Mechanisms that inhibit cell cycle progression and establish growth arrest are fundamental to tumor suppression and to normal cell differentiation. A complete understanding of these mechanisms should provide new diagnostic and therapeutic targets for future clinical applications related to cancer-specific pathways. This review will focus on the HMG-box protein 1 (HBP1) transcriptional repressor and its roles in cell cycle progression and tumor suppression. The work of several labs now suggests a new pathway for inhibiting G1 progression with exciting possible implications for tumor suppression. Our recent work suggests that the two previously unassociated proteins-the HBP1 transcription factor and the p38 MAP kinase pathway-may now participate together in a G1 regulatory network. Several recent papers collectively highlight an unexpected role and connection of the p38 MAP kinase-signaling pathway in cell cycle control, senescence, and tumor suppression. Together, these initially divergent observations may provide clues into a new tumor suppressive network and spur further investigations that may contribute to new diagnostic and therapeutic targets for cancer.