Lack of adequate appreciation of physical exercise's complexities can pre-empt appropriate design and interpretation in scientific discovery.

Two major issues are presented. First, a challenge is made by us that a misunderstanding of physiology has led to incomplete or wrong functional designations of genes in some cases. Normal physiological processes are dynamic, integrated and periodic, and, therefore, it is difficult to define normal physiological function by looking at a single time point or single process in a non-stressed subject. The ability of the organism to successfully respond to homeostatic disruptions defines normal physiology. Genes were selected for survival and to appropriately respond to stresses, such as physical activity. Omitting gene functions by restricting them to non-stressful conditions could lead to less than optimal primary preventions, treatments and cures for diseases. Physical exercise, as a stressor, should be used to better demonstrate the complete functional classifications of some genes. Second, the challenge from others of an 'exercise pill' as a mimetic of natural physical activity will be shown to be lacking a scientific basis. The concept of an 'exercise pill'/'exercise mimetic' demonstrates an inadequate appreciation of the complexities in integrating cell, tissue, organ and systems during both acute disruptions in homeostasis by a single bout of exercise, and longer-term chronic adaptations to different types of exercise such as resistance and endurance. It is our opinion that those promoting drugs targeting a single or few molecules should not redefine the term 'exercise' and exercise concepts in an attempt to sensationalize findings. Additionally, the scientific criteria that the authors demand to be met to legitimately use the terms 'exercise pill' and 'exercise mimetic' are presented.