Adiponectin is an adipose-tissue-derived hormone with anti-diabetic, anti-atherogenic and anti-inflammatory functions. Adiponectin circulates in the bloodstream in trimeric, hexameric and high-molecular-mass species, and different forms of adiponectin have been found to play distinct roles in the regulation of energy homoeostasis. The serum levels of adiponectin are negatively correlated with obesity and insulin resistance, yet the underlying mechanisms remain elusive. In the present review, we summarize recent progress made on the mechanisms regulating adiponectin gene transcription, multimerization and secretion. We also discuss the potential relevance of these studies to the development of new clinical therapy for insulin resistance, Type 2 diabetes and other obesity-related metabolic disorders.