Studies have linked obesity, metabolic syndrome, type 2 diabetes, cardiovascular disease (CVD), nonalcoholic fatty liver disease (NAFLD) and dementia. Their relationship to the incidence and progression of these disease states suggests an interconnected pathogenesis involving chronic low–grade inflammation and oxidative stress. Metabolic syndrome represents comorbidities of central obesity, insulin resistance, dyslipidemia, hypertension and hyperglycemia associated with increased risk of type 2 diabetes, NAFLD, atherosclerotic CVD and neurodegenerative disease. As the socioeconomic burden for these diseases has grown signficantly with an increasing elderly population, new and alternative pharmacologic solutions for these cardiometabolic diseases are required. Adipose tissue, skeletal muscle and liver are central endocrine organs that regulate inflammation, energy and metabolic homeostasis, and the neuroendocrine axis through synthesis and secretion of adipokines, myokines, and hepatokines, respectively. These organokines affect each other and communicate through various endocrine, paracrine and autocrine pathways. The ultimate goal of this review is to provide a comprehensive understanding of organ crosstalk. This will include the roles of novel organokines in normal physiologic regulation and their pathophysiological effect in obesity, metabolic syndrome, type 2 diabetes, CVD, NAFLD and neurodegenerative disorders.