The bioenergetic defects lie at the heart of metabolic disease, age-related disease, and cancer; however, what initiates the processes remain insufficiently understood. For the last several years since the previous keystone meeting on bioenergetics, the field has been transformed and growing because of several breakthroughs. For instance, new mechanisms of futile cycling were identified. Novel regulators of mitochondrial metabolism and their roles in metabolic diseases and cancer have been reported. The sensitivity and resolution of metabolomics, lipidomics, and proteomics technologies are rapidly increasing. Thus, there is momentum to organize a meeting that focuses on this exciting and emerging topic in the context of metabolic diseases, exercise, and cancer. Our specific goals for this meeting are to 1) addressing emerging questions in the field of bioenergetics in the context of metabolic diseases at molecular and organismal levels, 2) facilitating synergy between established and new investigators in the field of energy metabolism, and 3) providing new trainees with a better picture of critical knowledge gaps. We assembled inter-disciplinary speakers in the field of mitochondrial bioenergetics, cancer metabolism, exercise physiology, and metabolic diseases. This symposium will address key questions in the field, e.g., what initiates bioenergetic defects in metabolic organs? How do the defects lead to pathogenesis? How can we restore the bioenergetic defects to a healthy state? Together with the adipocyte biology symposium, the joint sessions also feature three topics – 1) recent technological innovation in metabolic flux analyses, 2) novel regulators of mitochondrial functions and 3) brown and beige adipocyte and the roles in energy homeostasis. We believe that these topics will create numerous new collaborations and cross-disciplinary interactions.