The preservation of a functional pancreatic β-cell mass has become a major point of research in type 2 diabetes (T2D) and the future therapies of T2D notably aim at protecting the β-cell from dysfunction and apoptotic death. β-cell proliferation, survival and insulin secretion are regulated by crucial transcription factors which are activated by signalling pathways engaged by nutrients, G-protein coupled receptors or tyrosine kinase receptors. Among these factors, the cAMP-responsive element-binding protein (CREB) has emerged as a key transcriptional element for the maintenance of an efficient glucose sensing, insulin exocytosis, insulin gene transcription and β-cell survival. CREB activates the transcription of target genes within the β-cells in response to a diverse array of stimuli including glucose, incretin hormones such as the glucagon-like peptide-1 (GLP-1) or the gastric inhibitory polypeptide (GIP), the pituitary adenylate cyclase-activating polypeptide (PACAP), or growth factors such as the insulin like growth factor-1 (IGF-1). All these stimuli phosphorylate CREB at a particular residue, serine 133, which is required for CREB-mediated transcription. However, the molecular mechanisms by which CREB activates gene transcription in β-cells vary according to the nature of the stimulus. These mechanisms involve different protein kinases, scaffold proteins and cofactors which allow CREB to specifically regulate the expression of crucial genes such as insulin, BCL-2, cyclin D1, cyclin A2 or IRS-2. In this review, we summarize the signalling pathways that lead to CREB phosphorylation in β-cells and the molecular features of each signalling pathway that rise specificity at the level of CREB activation and regulation.