Hepatitis B virus (HBV) is the most prevalent infectious agent that can induce severe liver disease. Patients infected with long-term HBV, including chronic, asymptomatic and occult forms, cannot clear HBV from infected hepatocytes completely. It is not clear why some people can clear the infection while others cannot. Furthermore, the main mechanisms responsible for progression of the infections are not fully understood. It has been hypothesised that differences in genetic and immunological parameters between patients and subjects who successfully clear HBV infections are responsible for inducing the long-term forms of the infection. Previous investigations showed that Toll-like receptors (TLRs) play important roles in immune responses, especially innate immunity, against viral infections, including hepatitis B. TLR9 detects intracellular viral dsDNA, which results in the activation of an immune response against HBV. However, defects in this system may result in an attenuated response ultimately leading to long-term HBV infections. Targeting the defects in TLR9 or reactivating the downstream pathways that are normally switched on by TLR9 in response to HBV infection is a new approach to the treatment of long-term HBV infection. However, the pathways and defects seen in patients with long-term HBV need to be thoroughly explored before therapeutics can be applied in the clinical setting. Furthermore, the apparently multigenic nature of long-term HBV infection suggests that treatment of patients may need to be personalised.