Obesity is a hereditary condition that affects millions of people and has serious health consequences. Despite recent advances in the understanding of the molecular biology controlling energy homeostasis and large efforts to uncover the genetic underpinnings of obesity in human populations, the exact molecular cause of weight gain in the majority of people remains unknown. By subscribing to the notion that the brain plays a critical role in the control of energy homeostasis and ultimately the genesis of obesity, we acknowledge that the greatest challenge following the identification of the genetic make up of obese individuals will be to understand how these molecular defects work in combination to alter the neurophysiology of those regions of the brain that control energy balance. To identify research strategies for the study of human obesity that complement positional cloning, we have developed a concept that we will refer to as neuroimagenomics (NIG), consisting of an iterative experimental approach combining neuroimaging and gene expression profiling of the human brain. We suggest that neuroimagenomics, which capitalizes on powerful and complementary brain imaging and genomic approaches to the problem, provides an especially promising way to investigate the molecular biology of obesity and assist in the discovery of novel drugs to treat this extraordinary public health problem.