The clinical course of persistent viral infections is usually chronic and recurrent, which may lead to development of tumor or autoimmune diseases, etc. Since persistent infectious diseases occur in a large number of patients, these infections not only are important issues for public health but also can cause heavy economic burden to the society. The factors involved in the “difficult－to－treat” viral persistent infections are related to the genomic characteristics of viruses, their interactions with host chromosomes, either via integration or by presence as episomes, and various inhibitory mechanisms of host immune responses mediated by viral enzymes or proteins. In addition, defects in host innate and (or) acquired immunity, deregulation of immune responsive network, and alterations in the local infected microenvironment are also involved to establish and maintain persistent viral infections. This review summarizes the viral and host factors in difficult－to－treat persistent viral infections, and presents some ideas and strategies for the treatment of persistent viral infections.