The mammalian target of rapamycin (mTOR) is a kinase that responds to a myriad of signals, ranging from nutrient availability and energy status, to cellular stressors, oxygen sensors and growth factors. The finely tuned response of mTOR to these stimuli results in alterations to cell metabolism and cell growth. Recent studies of conditional knockouts of mTOR pathway components in mice have affirmed the role of mTOR signaling in energy balance, both at the cell and whole organism levels. Such studies have also highlighted a role for mTOR in stem cell homeostasis and lifespan determination. Here, we discuss the molecular mechanisms of TOR signaling and review recent in vitro and in vivo studies of mTOR tissue-specific activities in mammals.