The term fatty liver identifies a liver in which lipids account for more than 5% of the livers wet weight. When fat accumulates, the lipids primarily stored as triglycerides (TG) result in steatosis and provide substrates for lipid peroxidation. Accumulation of neutral lipids in hepatocytes leads to micro- and macro-vesicular steatosis and to balloon-cell degeneration. Increased fat deposition in the liver is generally believed to be the result of an imbalance between fatty acids (FA) inflow/oxidation, and TG synthesis and excretion. Fat accumulation is not necessarily a pathological condition, but has been suggested to be the setting for more severe liver diseases, including nonalcoholic steatohepatitis (NASH) or cirrhosis. Since steatosis is notably present in the Western world, there is increased interest to know its potential consequences for the liver function. However, the information available to date about the impact of steatosis on the human liver metabolism is very scarce. Specifically, the impaired metabolism of a number of drugs has been associated with fatty liver. In relation to this, changes in some cytochrome P450 (CYP) enzymes have been found in livers of patients with steatosis, in vivo models of steatosis in experimental animals and in vitro models of fat-overloaded cells. These findings suggest an association between increased lipid deposition and impaired CYP enzymes. This paper presents an overview of the impact of steatosis in the livers drug-metabolizing capability. Moreover, the possible molecular mechanisms involved in the transcriptional regulation of the CYP expression in fatty liver are discussed.