Diabetes is a group of metabolic disorders resulting from defects in insulin secretion, insulin action, or both. It is characterized by high blood sugar levels over a prolonged period of time with disturbances of carbohydrate, protein, and fat metabolism. It is a global disorder affecting about half a billion or 536.6 million people worldwide, which is said to rise to 783.2 million by 2045. To maintain normoglycemia, pancreatic β-cells release insulin in proportion to the amounts of nutrients in the blood. Through a process of postnatal development, β-cells learn to connect insulin release to food cues. The insulin secretory response in mature β-cells adjusts to alterations in nutritional status. The interaction between transcriptional programs specific to each cell type and external stimuli is necessary for both β-cell maturation and functional adaptation. In this review, we examine the growing data that suggests lineage-determining and signal-dependent transcription factors (LDTFs and SDTFs, respectively) work together to regulate β-cell activity during development and homeostasis. In-depth knowledge of β-cell SDTFs and their corresponding signals would clarify the processes involved in β-cell maturation and functional adaptation, directly affecting diabetes treatments and the production of mature β-cells from stem cells.