Chronic hepatitis B (CHB) is a worldwide public health problem which represents an enormous economic and social burden. Convincing evidence has shown that persistent active viral replication is an independent predictor of disease progression. Therefore, sustained suppression of HBV replication is the cornerstone for preventing the progression of disease and prolonging survival in patients with CHB. Pivotal clinical trials and real-world studies show that nucleos(t)ide analogues (NAs) are potent suppressors of HBV DNA replication with very good safety profiles. Although 1-year treatment with NAs only results in a modest rate of HBeAg seroconversion, extended treatment could increase this rate. Profound suppression of HBV DNA can result in histological improvement and a clinical benefit with a decrease in disease progression in patients with compensated or decompensated cirrhosis. Treatment must be begun with a highly potent and low resistant regimen to obtain long-term suppression of viral replication. An alternative solution may be a roadmap approach in which an inexpensive antiviral drug is started and another drug is added-on or switched-to if there is a suboptimal on-treatment decrease in HBV DNA. Clinical evidence has shown that once HBV DNA is suppressed and long-term HBeAg seroconversion is achieved, NAs can be stopped. In summary, high antiviral efficacy, excellent tolerance, extensive applicability, clearly proven histological improvement and long-term clinical benefit all make NAs the preferred choice for the management of CHB in most patients.