Hepatic encephalopathy (HE) is a challenging clinical complication of liver dysfunction with a wide spectrum of neuropsychiatric abnormalities that range from mild disturbances in cognitive function and consciousness to coma and death. The pathogenesis of HE in cirrhosis is complex and multifactorial, but a key role is thought to be played by circulating gut-derived toxins of the nitrogenous compounds, most notably ammonia. Therapeutic treatment options for HE are currently limited and have appreciable risks and benefits associated with their use. Management of HE primarily involves avoidance of precipitating factors, limitation of dietary protein intake, and administration of various ammonia-lowering therapies such as non-absorbable disaccharides and select antimicrobial agents. Non-absorbable disaccharides, such as lactulose, have traditionally been regarded as first-line pharmacotherapy for patients with HE. However, multiple adverse events have been associated with their use. In addition, recent literature has questioned the true efficacy of the disaccharides for this indication. Neomycin, metronidazole and vancomycin may be used as alternative treatments for patients intolerant or unresponsive to non-absorbable disaccharides. Antimicrobials reduce bacterial production of ammonia and other bacteria-derived toxins through suppression of intestinal flora. Neomycin has been reported to be as effective as lactulose, and similar efficacy has been reported with vancomycin and metronidazole for the management of HE. However, the adverse effects frequently associated with these antimicrobials limit their use as first-line pharmacological agents. Neomycin is the most commonly used antimicrobial for HE and, although poorly absorbed, systemic exposure to the drug in sufficient amounts causes hearing loss and renal toxicity. Long-term neomycin therapy requires annual auditory testing and continuous monitoring of renal function. Long-term use of metronidazole has been associated with neurotoxicity in patients with cirrhosis, including dose-dependent peripheral neuropathy. Vancomycin may be a safer option for HE in patients with chronic liver disease; however, limited experience, possible bacterial overgrowth and risk for enteric bacteria resistance preclude the routine use of vancomycin for HE. Rifaximin is a novel antimicrobial agent with a wide spectrum of activity that has shown promise as an alternative antimicrobial treatment option for HE. Several clinical trials have compared rifaximin to the disaccharides, lactulose and lactitol, and the antimicrobial neomycin. Rifaximin appears to be at least as effective as conventional drug therapy and has been associated with fewer adverse effects due to its limited systemic absorption. The available clinical data appear to support a favourable benefit-risk ratio for rifaximin, which has shown efficacy with an improved tolerability profile. Future studies are needed in order to truly characterize its cost effectiveness in today's healthcare environment. Other less frequently utilized alternative treatment options include administration of benzodiazepine receptor antagonists, branched-chain amino acids, ornithine aspartate, zinc supplementation, sodium benzoate, dopamine receptor agonists, acarbose and probiotics. Presently, there is relatively limited clinical data supporting their routine use in HE.