In 1991, Hans Berg and colleagues published the first research investigation using unilateral lower limb suspension (ULLS) as a human model to study the influence of unloading on skeletal muscle. ULLS requires a participant to perform all activities with axillary crutches while wearing one thick-soled shoe. The elevated shoe eliminates ground contact with the adjacent foot, thereby unloading the lower limb. Today, ULLS is a well-known ground-based analog for microgravity. The present review will synthesize the physiological findings from investigations using ULLS to study the deleterious effects of unloading. Compromised human performance and the neuromuscular, musculoskeletal and circulatory mechanisms leading to altered function will be a major emphasis of the work. Results from prolonged bed rest will also be included in order for general comparisons to be made between analogs. Finally, the efficacy of exercise to mitigate the negative consequences of unloading is presented.