Obesity and its associated diseases are expected to affect more than 1 billion people by the year 2030. These figures have sparked intensive research into the molecular control of food intake, nutrient distribution, storage and metabolism--processes that are collectively termed energy homeostasis. Recent decades have also seen dramatic developments in our understanding of gene regulation at the signalling, chromatin and post-transcriptional levels. The seemingly exponential growth in this complexity now poses a major challenge for translational researchers in need of simplified but accurate paradigms for clinical use. In this Review, we consider the current understanding of transcriptional control of energy homeostasis, including both transcriptional and epigenetic regulators, and crosstalk between pathways. We also provide insights into emerging developments and challenges in this field.