The appropriate clinical management of coinfections implicating one or more of the major viral hepatitis agents such as hepatitis B virus (HBV) and hepatitis C virus (HCV), with or without concomitant infection with human immunodeficiency virus (HIV), is a matter of concern. Given that the routes of transmission of all these agents are often overlapping, and due to their high prevalence among certain groups at risk, it is common to be confronted with patients with active, simultaneous infection of two, or even more, such pathogens. Despite this, the number of articles and, most importantly the number of randomized controlled trials enrolling these patients, is low—with the exception of the HCV/HIV-coinfected population. I am particularly glad that we could assemble three manuscripts focusing on some of these issues (the management of patients coinfected with HBV and hepatitis D virus will form the topic of an independent issue). Professor Wedemeyer and coworkers from Hannover summarize what is known about the management of patients coinfected with HBV and HCV. This dual infection often presents a fluctuating, mutual interference between these two hepatotropic viruses: for this reason, the optimal timing and modality of antiviral therapy warrant a careful approach and subtle reasoning, but appropriate studies are lacking. A second paper, from Dr Soriano and colleagues from Madrid, reports on the most recent findings concerning individuals with simultaneous HCV and HIV infections. This subgroup of chronic hepatitis C patients is of particular concern, not only because they present an accelerated progression of the underlying liver disease but also because of their poor response rate to antivirals relative to persons infected with HCV alone. Finally, a contribution from Dr Boesecke and Professor Rockstroh, from Bonn, discusses the complex therapeutic approach of HBV/HIV coinfection. Here, the diagnostic algorithms and therapeutic challenges are discussed in detail. In particular, it is underlined how many nucleoside and nucleotide analogs have dual activity against these two agents, something that entails the risk of the unwanted selection of antiviral agent–resistant strains. All three articles make quite clear one point: many questions remain unanswered in the field of viral coinfections, especially when it comes to therapeutic trials.