Entecavir has demonstrated safety and efficacy in the treatment of chronic hepatitis B infection. It is the prototype for the cyclopentane class of nucleoside/nucleotide chronic hepatitis B antiviral agents. It has a high potency and, due to its structural formula and mechanism of action, entecavir is associated with emergence of minimal resistance in the long-term treatment of nucleoside-naive patients. Research suggests that long-term treatment may be required for chronic hepatitis B patients, especially those who acquire HBV early in life, to achieve maximum viral suppression and improve outcomes. Several recent studies have evaluated the long-term safety, efficacy and development of resistance in nucleoside-naive patients treated with entecavir. Results indicate that the long-term use of entecavir is well tolerated and associated with continuous clinical improvement -- with an increasing number of patients achieving undetectable levels of HBV DNA, HBeAg seroconversion and minimal resistance. These data underscore the position of entecavir for first-line therapy and highlight its role in the long-term treatment of chronic hepatits B.