Statins, a group of drugs used for the treatment of hypercholesterolemia, have adverse effects on skeletal muscle. The symptoms of these effects range from slight myalgia to severe rhabdomyolysis. The number of patients currently taking statins is estimated to be several millions worldwide. However, the mechanism of statins' myotoxic effects is unclear. Statins inhibit biosynthesis of mevalonate, a rate-limiting step of cholesterol synthesis, by inhibiting HMG-CoA reductase. Mevalonate is also an essential precursor for producing isoprenoids such as farnesylpyrophosphate and geranylgeranylpyrophosphate. These isoprenoids are especially important for anchoring small GTPases to the membrane before they function; e.g., Ras GTPases modulate proliferation and apoptosis, Rho GTPases control cytoskeleton formation, and Rab GTPases are essential for intracellular vesicle trafficking. Inactivation of these small GTPases alters cellular functions. Recently, we successfully reproduced statin-induced myotoxicity in culture dishes using in vitro skeletal muscle systems (e.g., skeletal myotubes and myofibers). This review summarizes our findings that statins induce depletion of isoprenoids and inactivation of small GTPases, especially Rab, which are critical for statin-induced myotoxicity. Although further study is required, our findings may contribute to the prevention and treatment of statins' adverse effects on skeletal muscle and development of safer anti-hypercholesterolemia drugs.