A major goal of 21st century science is to protect human health from the growing mismatch between ancient behavioural instincts and modern socio-economic reality. This is especially vital for basic instinctive drives such as appetite, which lead to overeating when food is readily available. The resulting obesity is responsible for 100,000s of premature deaths per year in Europe and North America, and this number is rapidly rising. Sleep is another powerful instinct which substantially contributes to premature human death, for example from car accidents caused by tiredness. Thus “self-destructive” behaviours caused by inappropriate activation of feeding and sleep drives take a devastating social and economic toll in developed countries, and there is a huge unmet need for effective therapies in this area. To design these therapies, we need to understand the brain mechanisms of instinctive drives. However, brain circuits regulating appetite and sleep have only been delineated in the past few years, and their principles of operation are poorly understood at present. The broad aim of my newly-established laboratory is to fill this gap in knowledge. To understand neural signals controlling instinctive drives, and their relationship to well-being and disease, the following questions must be answered: 1) how do neurons that control appetite and sleep generate their electrical and chemical signals? ) how do these neurons interact with each other? 3) how are these neurons altered in disorders of energy balance and sleep? Our objective for the next five years is to address these key unknowns by focusing on neurons known to be unequivocally important for normal sleep and appetite, the orexin and MCH neurons of the lateral hypothalamus.