It is widely assumed that the fundamental cause of obesity is an energy imbalance between calories consumed and calories expended (i.e., the energy balance theory; EBT). However, this century-old obesity paradigm must be fallacious. According to known laws of physics, chronic positive mass balance is the actual etiology of obesity, not positive energy balance. The relevant physical law in terms of body mass regulation is the Law of Conservation of Mass, not the Law of Conservation of Energy. It is important to understand that energy balance and mass balance are separate balances in the human body. Calories represent the heat release upon food oxidation, and as such, calories have no impact on body mass. Body mass can only change due to net mass flow; thus, the only food property that can augment body mass is its nutrient mass, not its energy content. A recently proposed mass balance model (MBM) describes the temporal evolution of body weight and body composition under a wide variety of feeding experiments, and it seems to provide a highly accurate description of the very best experimental human feeding data. By shifting to a mass balance paradigm of obesity, a deeper understanding of this disease may follow in the near future. The purpose of this living review is to present the core issues of the upcoming paradigm shift as well as some practical applications related to the topic.