A typical target discovery experiment would comparatively analyze two or more proteomes by ABPP to identify enzymes with differing levels of activity (Figure 1) . The differentially expressed serine hydrolases in healthy and diseased samples can be hypothesized to regulate the host-virus interaction. The testing of such hypotheses, of course, requires further experimentation for validation (e.g., functional interference of the target enzyme). ABPP has been used to profile a number of enzyme classes including proteases, hydrolases, oxidoreductases, and isomerases in the process of host-virus interaction Schlieker et al., 2005; Wang et al., 2006; Gredmark et al., 2007; Jarosinski et al., 2007; Shah et al., 2010) . Profiling of hydrolases in Huh7 cells replicating HCV identified CES1 (carboxylesterase 1) as a differentially active enzyme which has an important role in HCV propagation (Blais et al., 2010) . We have examined the activity of serine hydrolases during reovirus, Influenza A, and Sindbis virus replication in cell culture in different cell lines. Differential serine hydrolase activities were induced by different viruses and alterations of serine hydrolases were dependent on the time course of viral infection. Several of these differentially active serine hydrolases represent possible virus-host interactions that could be targeted for development of antivirals.