In this talk I will describe how the study of humans with rare functionally impactful genetic variants has provided novel insights into a range of human endocrine and metabolic phenotypes. In particular,  I will discuss-

i) the control of energy balance and its disturbances in obesity and how those investigations have also led to new insights into the link between nutritional state and sexual maturation;

ii) the control of insulin sensitivity and its disturbances in states of insulin resistance; this will include information about a novel class of adipose tissue dysfunction which appears to be a prevalent contributor to metabolic ill-health;

and

iii) how human genetics has contributed to a deeper understanding of the nausea and vomiting of pregnancy, leading to a point where trials of novel therapeutic and preventive strategies have been launched.