The obesity epidemic has evolved into an ever expanding serious global health concern. Several physiological as well as environmental factors have contributed to the rise in obesity incidence. Obesity or being overweight results from an energy imbalance characterized by an excess of caloric intake more often than not combined with a reduced energy expenditure, for example due to physical inactivity. Nutrient status is communicated via circulating gut hormones, which all act on the brain to regulate short- and long-term appetite and the body's metabolism and this brain-gut axis communication is dysregulated under metabolic conditions, such as obesity. Ghrelin is the only peripheral derived hormone, which exerts an orexigenic effect via the modulation of central circuitries and has therefore received considerable focus in the pharmaceutical industry for the development of anti-obesity therapeutics. Two subtypes of the ghrelin receptor have been reported to date, the growth hormone secretagogue (GHS-R1a) receptor 1a isoform, which is activated by acylated ghrelin, and the truncated isoform GHS-R1b, which is functionally inactive. Interestingly, the GHS-R1b receptor has been shown to exert a dominant-negative effect on GHS-R1a receptor functioning via the formation of a GHS-R1a/1b dimer. The GHS-R1a is expressed in multiple brain regions with ghrelin’s orexigenic effect on homeostatic food intake being mainly mediated in the arcuate nucleus of the hypothalamus and hedonic aspects being mediated via GHS-R1a receptors in the mesolimbic dopaminergic circuitry. In this review we discuss the role of ghrelin in the hypothalamic regulation of appetite and highlight the additional dimension of the ghrelin/GHS-R1a receptor axis as a target in obesity via manipulation of the ghrelin-mediated non-homeostatic rewarding aspect of food intake behaviour. In addition, we review the current understanding of the role of the ghrelin receptor isoforms as targets in obesity and discuss the potential of heterodimers in the development of more specific anti-obesity therapeutics.