Abstract: Type 2 diabetes, an epidemic disorder characterized by high blood glucose level associated with microvascular complications, is one of the main causes of human suffer across the globe, with no effective medicine up to now. AMP-activated protein kinase(AMPK), a highly conserved serine/threonine protein kinase, is a key sensor and regulator of intracellular and whole-body energy metabolism. Small molecule AMPK direct activators have been proven to lower blood-glucose, which is a promising candidate for the treatment of type 2 diabetes. The progress on the research of small molecule AMPK direct activators in recent years is summarized in this paper.