In addition to neuraminidase inhibitors and other drugs that directly target viral replication, a number of adjunctive and immunomodulatory therapies are currently under evaluation for the treatment of influenza. These novel treatments, which focus either on pathophysiological aspects of influenza virus infection or the neutralization of virus with antibodies, are the subject of this review. Cytokine dysregulation has been observed in patients with severe influenza, such as avian influenza A (H5N1) and pandemic 2009 influenza A (H1N1pdm09) virus infections, but the role of immunomodulatory therapy is unclear, due to lack of data from randomized controlled trials (RCTs). Convalescent plasma appears to be useful as an adjunctive therapy for the treatment of H5N1 and H1N1pdm09 infections. Until lately, data interpretation was limited to case reports and studies of non-randomized design, but a recent RCT found that patients with severe influenza A (H1N1pdm09) who were treated with hyperimmune immunoglobulin from persons who had survived the same disease had a lower peak viral load and lower mortality than controls, providing treatment was begun within 5days of symptom onset. The efficacy of agents with potential immunomodulating effects, including intravenous immunoglobulin, N-acetylcysteine, acute use of statins, macrolides, peroxisome proliferator-activated receptors agonists, celecoxib and mesalazine, and the role of plasmapheresis and hemoperfusion as rescue therapy, deserve more investigation and where feasible, studies by RCTs. Prospective observational studies have shown that systemic corticosteroids increase morbidity (e.g., secondary infections) and mortality in H1N1pdm09 influenza. This article forms part of a symposium in Antiviral Research on "Treatment of influenza: targeting the virus or the host."