Accumulating evidence supports the use of specific diagnostic tests and antiviral therapies for seriously ill patients with influenza. Among available diagnostic tests, reverse-transcriptase polymerase chain reaction is faster than culture and more sensitive than commercial antigen assays. Current neuraminidase inhibitors were approved on the basis of their efficacy in ambulatory patients, but seriously ill patients who receive these agents are less likely to die, even when treatment is initiated >48 h after symptom onset. For patients hospitalized with suspected influenza, it is unclear which circumstances warrant diagnostic testing and which warrant the use of empirical therapy. Rapid antigen assays may reduce the unnecessary use of other tests and medications but are relatively insensitive, thus eliminating many patients with influenza as candidates for treatment. Empirical antiviral therapy ensures that all patients receive treatment promptly, at a cost equivalent to that of diagnostic tests alone, but results in the receipt of treatment by many patients without influenza. For patients hospitalized with suspected influenza, clinicians need to combine these approaches in order to optimize patient care.