Spontaneous bacterial peritonitis (SBP) is the prototypical ascitic fluid infection occurring in patients with advanced liver disease and ascites. The key to successful treatment of SBP is a knowledge of appropriate antibiotic regimens and an understanding of the setting in which infection develops, particularly those individuals at high risk for infection. A high index of suspicion should lead to early diagnostic paracentesis and ascitic fluid analysis. Treatment of SBP involves the use of non-nephrotoxic broad-spectrum antibiotics expected to cover the typical bacterial flora associated with SBP. SBP typically involves infection with a single organism, with Escherichia coli, Klebsiella spp, and Streptococcus spp responsible for nearly three fourths of cases. The treatment of choice is cefotaxime 2 g given intravenously every 8 hours for a total of 5 days. The antibiotic regimen is adjusted based on the results of ascitic fluid cultures. Other antibiotic regimens for SBP are less well studied. Given the significant morbidity and mortality rates associated with SBP, efforts to prevent its development and recurrence with antibiotic prophylaxis are warranted. The most extensively studied form of prophylaxis involves selective intestinal decontamination (SID) with the oral fluoroquinolone norfloxacin. Individuals with low-protein ascites (ascitic fluid total protein < 1g/dL) benefit from SID with norfloxacin 400 mg daily during times of hospitalization. Long-term primary prophylaxis during outpatient management of individuals awaiting liver transplantation with severe ascites and advanced liver failure should also be considered. Patients with cirrhosis and upper gastrointestinal bleeding should receive norfloxacin 400 mg twice daily for 1 week following their bleed. Those individuals surviving an episode of SBP should be treated with norfloxacin 400 mg daily until the risk of SBP is removed by definitive resolution of the ascites or liver transplantation surgery. Although the infection-related mortality associated with SBP has decreased to less than 10%, hospitalization-related mortality remains as high as 30% as a result of the severe underlying liver disease in which the infection arises and the marked generation of cytokines and nitric oxide resulting from the infection. Recently, the simultaneous administration of intravenous albumin and antibiotics for SBP has been shown to result in the decreased development of azotemia and hospitalization-related mortality. Further improvement in the outcomes of SBP will require treatments targeting this cytokine cascade rather than the development of more potent antibiotics.