The epidemics of obesity and type 2 diabetes have led to intensive investigation of the underlying mechanisms of these diseases and their main complications such as cardiovascular diseases and non-alcoholic fatty liver disease. This search has contributed to better understand how organs and tissues communicate with each other in the so-called inter-organ crosstalk. Adipose tissue, the liver, or skeletal muscle can actively release secreted factors termed "organokines" which can interact with other distant targets in complex networks. More recently, other novel mediators of inter-organ crosstalk such as extracellular vesicles and their non-traditional cargoes as miRNAs and lncRNAs are gaining importance and represent potential therapeutic targets. In the present chapter we summarize some of the current knowledge on inter-organ communication with a focus on adipose tissue-released factors and their modulation on other organs and tissues like pancreas, liver, skeletal muscle, the cardiovascular system, and the gut in the context of obesity and its progression to insulin resistance. We also provide a perspective on mediators of inter-organ crosstalk as potential therapeutic targets.