Glycogen was first identified in muscle over a century and a half ago. Even though we have known of its existence and its role in metabolism for a long time, recognition of its ability to directly and indirectly modulate signaling and the adaptation to exercise is far more recent. Acute exercise induces a number of changes within the body (i.e. sympathetic nervous system activation and elevation of plasma free fatty acids) and muscle (increased AMP-activated protein kinase activity and fat metabolism) that may underlie the long-term adaptation to training. These changes are also affected by glycogen depletion. This review discusses the effect of exercise in a glycogen-depleted state on metabolism and signaling and how this affects the adaptation to exercise. Although 'training low' may increase cellular markers associated with training and enhance functions such as fat oxidation at sub-maximal exercise intensities, how this translates to performance is unclear. Further research is warranted to identify situations both in health and athletic performance where training with low glycogen levels may be beneficial. In the meantime, athletes and coaches need to weigh the pros and cons of training with low carbohydrate within a periodized training program.