The immune response during HBV infection plays a pivotal role in the outcome and progression of disease. This is illustrated by the repeated observation of a differential response in terms of the strength and the breadth of the immune response between patients who resolve HBV infection spontaneously and those that develop persistent CHB. This defective immune response which characterizes CHB is an opportune target for manipulation to overcome paralysis and represents an area of active investigation by our group. Targeting host factors exploited by the virus to promote its replication is a parallel avenue we are also actively pursuing. These strategies more commonly known as host-targeted therapy may confer several advantages, in comparison to traditional virus-targeted treatments, including a high resistance barrier, broad pan-genotypic activities, higher potency and lower toxicity. Recent immune-mediated and host protein therapeutic targets identified and reported for chronic Hepatitis B include Programmed-Death-1, Cyclophillins, Interferon-l and pro-fibrogenic mediator Osteopontin.