© 2016 American College of Cardiology Foundation Adipokines are peptides, secreted by adipocytes and other cell types with targets in other tissues, participating in a complex network of humoral factors involved in obesity, insulin resistance, and cardiovascular (CV) disease. This review describes recent information about adipokine effects on the CV system. Rather than simply providing a listing of adipokines and their respective effects, network analysis is used to enhance understanding. Various relationships and emergent processes in the adipokine-CV system network are discussed, with the most significant interactors being responses to hypoxia, regulation of cell migration, effects on blood coagulation, and platelet activation. Clinical translation is provided through network representations of the “obesity paradox,” “metabolically healthy obese,” “metabolic syndrome,” and beneficial role of lifestyle medicine. As more translatable information about the larger adipokine-CV-lifestyle network is acquired from laboratory and clinical research, the strategic and precise role of lifestyle intervention can be fashioned to improve CV outcomes.