Physiologically, insulin secretion is subject to a dual, hierarchal control by triggering and amplifying pathways. By closing ATP-sensitive K⁺ channels (K_ATP channels) in the plasma membrane, glucose and other metabolized nutrients depolarize β-cells, stimulate Ca²⁺ influx, and increase the cytosolic concentration of free Ca²⁺ ([Ca²⁺]_i), which constitutes the indispensable triggering signal to induce exocytosis of insulin granules. The increase in β-cell metabolism also generates amplifying signals that augment the efficacy of Ca²⁺ on the exocytotic machinery. Stimulatory hormones and neurotransmitters modestly increase the triggering signal and strongly activate amplifying pathways biochemically distinct from that set into operation by nutrients. Many drugs can increase insulin secretion in vitro, but only few have a therapeutic potential. This review identifies six major pathways or sites of stimulus-secretion coupling that could be aimed by potential insulin-secreting drugs and describes several strategies to reach these targets. It also discusses whether these perspectives are realistic or theoretical only. These six possible β-cell targets are 1) stimulation of metabolism, 2) increase of [Ca²⁺]_i by closure of K⁺_ATP channels, 3) increase of [Ca²⁺]_i by other means, 4) stimulation of amplifying pathways, 5) action on membrane receptors, and 6) action on nuclear receptors. The theoretical risk of inappropriate insulin secretion and, hence, of hypoglycemia linked to these different approaches is also envisaged.