Epidemiology has associated physical inactivity with 35 detrimental conditions/diseases; they are: accelerated secondary aging, premature death, low cardiorespiratory fitness, sarcopenia, metabolic syndrome, obesity, insulin resistance, prediabetes, type 2 diabetes, nonalcoholic fatty liver disease, coronary heart disease, peripheral artery disease, hypertension, stroke, congestive heart failure, endothelial dysfunction, arterial dyslipidemia, hemostasis, deep vein thrombosis, cognitive dysfunction, depression and anxiety, osteoporosis, osteoarthritis, balance, bone fracture/falls, rheumatoid arthritis, colon cancer, breast cancer, endometrial cancer, gestational diabetes, preeclampsia, polycystic ovary syndrome, erectile dysfunction, pain, diverticulitis, constipation, and gallbladder diseases. Deteriorating function with physical inactivity underlies some of the above conditions. After 20 days, healthy young men in the classical Dallas bed rest study had 11% lower heart volumes, 26% lower maximal cardiac outputs, 29% lower maximal stroke volumes, and 28% lower maximal oxygen consumptions. Microgravity of 1-yr space flight produces hipbone loss that would take 10 years to occur on Earth, illustrating gravity’s role with physical inactivity. A 3rd example is reduced daily steps. Healthy young men who reduced their daily steps from 10,501 to 1,344 for a 2-wk period displayed a clustering of metabolic alterations that included an increased insulin response to an oral glucose tolerance test, increased plasma triglyceride response to an oral fat tolerance test, a 7% increase in visceral fat, and a 0.5-kg loss of lean leg mass. A cellular basis was decreased insulin-stimulated ratio of pAktthr308/total Akt in vastus lateralis muscle after step reduction. Two animal models utilized by us to delineate the molecular basis of inactivity will be described. In the first model, rats have been selectively bred now for 7 generations to separate and contrast the phenotypes of motivation to voluntarily run long distances (HVR) vs. the motivation to voluntarily run low distances (LVR). An average 6-fold distance in voluntary running now separates HVR and LVR selected lines. HVR had reduced voluntary running after injection of D1 dopamine receptor agonists and antagonists into the nucleus accumbens of the rat brain, while LVR had no responses (Physiol Behav 105:661, 2012). The second model locks wheels for voluntary running (WL) resulting in elimination of daily running. The mRNAs and proteins for the mechanosensor genes Ankrd2 and Csrp3 fell in young, growing rats. Relative to WL5h controls, plantaris muscle Ankrd2 and Csrp3 mRNAs were lower at WL53h, WL173h, and SED; Ankrd2 protein tended to decrease at WL53h (p = 0.054) and Csrp3 protein was less in WL173h and SED rats (J Appl Physiol Epub Jan 26, 2012).