Nonalcoholic steatohepatitis (NASH) has become a major cause of cirrhosis and liver-related deaths worldwide. NASH is strongly associated with obesity and the metabolic syndrome, conditions that cause lipid accumulation in hepatocytes (hepatic steatosis). It is not well understood why some, but not other, individuals with hepatic steatosis develop NASH. The factors that determine whether or not NASH progresses to cirrhosis are also unclear. This review summarizes key components of NASH pathogenesis and discusses how inherent and acquired variations in regulation of these processes impact the risk for NASH and NASH cirrhosis.