Adiponectin, an adipokine secreted by the white adipose tissue, plays important roles in regulating glucose and lipid metabolism and controlling energy homeostasis in insulin sensitive tissues. A decrease in the circulating level of adiponectin has been linked to insulin resistance, type 2 diabetes, atherosclerosis and metabolic syndrome. Adiponectin exerts its effects through two membrane receptors, AdipoR1 and AdipoR2. APPL1 is the first identified protein that directly interacts with adiponectin receptors. APPL1 is an adaptor protein with multiple functional domains: the Bin1/amphiphysin/rvs167 (BAR), pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains. The PTB domain of APPL1 directly interacts with the intracellular region of adiponectin receptors. Through this interaction, APPL1 mediates adiponectin signaling and its effects on metabolism. APPL1 also functions in insulin signaling pathway and is an important mediator of adiponectin-dependent insulin sensitization in skeletal muscle. Adiponectin signaling through APPL1 is necessary to exert its anti-inflammatory and cytoprotective effects on endothelial cells. APPL1 also acts as a mediator of other signaling pathways by directly interacting with membrane receptors or signaling proteins, thereby playing critical roles in cell proliferation, apoptosis, cell survival, endosomal trafficking, and chromatin remodeling. This review mainly focuses on our current understanding of adiponectin signaling in various tissues, the role of APPL1 in mediating adiponectin signaling and also its role in the crosstalk between adiponectin-insulin signaling pathways.