In summary, i) the complete congenital lack of MC3R does not result in any substantial increase in BMI in humans and therefore, in contrast to several other genes in the leptin melanocortin pathway, MC3R should not be included in diagnostic panels for “monogenic obesity”; ii) a functionally impaired missense variant in MC3R is common in labrador retriever dogs, where it is associated with lower body weight and does not predispose to obesity; and iii) MC3R status influences the timing of puberty across all three species studied. Here, MC3R is linked to obesity due to melanocortin 4 receptor deficiency.