Appetite and satiety are mediated by complex neuroendocrine signalling pathways involving over 40 hormones, neuropeptides, enzymes, other chemical messengers and their receptors. Research efforts continue to expand understanding of the role of signalling molecules between central hypothalamic nuclei and peripheral enteroendocrine cells; and discoveries of novel networks and messengers provide new biological insights on how to manipulate appetite–satiety pathways. Despite the vast array of peptides that are potentially useful for anti-obesity drug development, only four classes of agents are approved: (i) catecholamine stimulants; (ii) serotonin and noradrenaline reuptake inhibitors; (iii) lipase inhibitors; and (iv) more recently cannabinoid-1 receptor antagonists. Clinical effects of these drugs confer modest improvements, and side effects negatively impact long-term treatment course. This paper suggests single target pharmacological interventions are possibly hampered by the myriad of alternate orexigenic peptidic signals that drive hyperphagia, hence a multiple target model or combination treatment approach is proposed to offer greater therapeutic potential in modulating appetite and managing weight.