Non-alcoholic fatty liver disease (NAFLD) is currently evolving as the most common liver disease worldwide. It may progress to liver cirrhosis and liver cancer and is poised to represent the most common indication for liver transplantation in the near future. The pathogenesis of NAFLD is multifactorial and not fully understood, but it represents an insulin resistance state characterized by a cluster of cardiovascular risk factors including obesity, dyslipidemia, hyperglycemia, and hypertension. Importantly, NAFLD also has evolved as independent risk factor for cardiovascular disease. Unfortunately thus far no established treatment does exist for NAFLD. The bile acid-activated nuclear farnesoid X receptor (FXR) has been shown to play a role not only in bile acid but also in lipid and glucose homeostasis. Specific targeting of FXR may be an elegant and very effective way to readjust dysregulated nuclear receptor-mediated metabolic pathways. This review discusses the body's complex response to the activation of FXR with its beneficial actions but also potential undesirable side effects. 1. Introduction One characteristic of our modern civilization is the easy and unlimited access to unhealthy and caloric dense food. A typical American diet furnishes the liver with ~20？g of fat each day, equivalent to one-half of the total triglyceride content of the liver. In combination with little need for physical activity due to technological advances, one consequence of our sedentary and excessive lifestyle is non-alcoholic fatty liver disease (NAFLD). NAFLD is a major health problem affecting up to 60 million Americans and evolving as the most common liver disease worldwide [1, 2]. This is several-fold higher than other common chronic liver diseases such as hepatitis C and alcohol-related liver disease. While the majority of subjects with NAFLD are obese, the condition can occur in the absence of obesity or other features of the metabolic syndrome. In patients with diabetes and morbid obesity the prevalence of NAFLD has been shown to be as high as 62% and 96%, respectively [3, 4]. The earliest stage of NAFLD is fatty liver that is defined as the presence of cytoplasmic triglyceride droplets in more than 5% of hepatocytes [5]. Although often self-limited, in 12–40% it can progress to non-alcoholic steatohepatitis (NASH) [6]. NASH is distinguished from simple fatty liver by the presence of hepatocyte injury such as hepatocyte ballooning and apoptosis, an inflammatory infiltrate, and/or collagen deposition. Over a time period of 10–15 years, 15% of patients with NASH
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