Cell signaling pathways intricately regulate cellular functions, impacting tumorigenesis and autoimmune responses. Posttranslational modifications like phosphorylation and ubiquitination modulate these pathways, often linked to tumorigenesis. Signal transduction, crucial for cell resilience, involves a molecular network responding to extracellular stimuli. Cell communication, mediated by messengers and receptors, regulates processes like division, migration, and immunity. Single-celled organisms also rely on signaling for survival and environmental responses. Receptors, especially GPCRs, are pivotal, in influencing drug development. Understanding these mechanisms informs cancer therapeutics and drug discovery. G-protein-coupled receptors (GPCRs) mediate cellular responses through a seven-helix structure. This signaling pathway influences diverse cellular processes, including sensory responses and hormonal regulation. GPCR stimulation also activates CREB signaling, impacting gene expression. The cAMP-dependent pathway is essential in organisms, controlling functions like heart rate, cortisol secretion, and energy metabolism, influencing memory, heart function, and kidney water absorption. Its activation can rapidly affect enzymes and gradually regulate gene expression, making it a focus of research to comprehend its role, while dysregulation may contribute to cancer development via uncontrolled cell proliferation. The cAMP–PKA–CREB pathway exerts a tumor-promoting function in various human tumors. Anomalously heightened activation of this pathway, along with its interplay with other signaling pathways, is intricately linked to the processes of tumorigenesis, invasion, metastasis, and the development of drug resistance. Currently, only a small fraction, specifically 5%, of drug-related targets in cancer successfully transition from preclinical to clinical stages, with only a subset making it to the patient’s bedside. The primary culprits behind this low success rate are intratumor heterogeneity and limitations in preclinical cancer models. Cyclic-AMP-response element-binding protein (CREB), identified as a proto-oncogene in various tumor types, plays a crucial role in tumor maintenance and progression. Given its significance in tumor pathophysiology, numerous compounds inhibiting CREB have been developed and tested over the years. This chapter emphasizes the crucial involvement of cAMP–PKA–CREB signaling in various types of cancers and the process of tumorigenesis. Additionally, potential approaches to target this pathway for cancer therapy are explored and discussed.