The Penn Center for Molecular Discovery, as part of the NIH Molecular Libraries Screening Centers Network (MLSCN), offers a combination of well-plate HTS, zebrafish screening, and microarray-based compound profiling. Using microarrayed nanoliter droplets of compounds, various assays of proteases, kinases, and phosphatases can be conducted in nanoliter reaction volumes. When chemical libraries are printed with glycerol, the nanodroplets are easily and rapidly activated with picoliter quantities of enzymes, substrates, and cofactors using aerosol deposition. These reactions are probed by multi-color laser scanners to provide high Z' at extremely low cost. Furthermore, these HTS reactions can be assembled on metal plates where nanoliter-scale reactions were analyzed by MALDI-TOF mass spectrometry with 10 fmole sensitivity. In chemical-biology applications, these microarrays have proven useful for mapping the protease-substrate proteome. A 722-member fluorogenic library [Ala-P3-P2-(Arg/Lys)-coumarin] was microarrayed and screened against over 20 proteases. Active site function on the substrate library was nearly identical for human, bovine, and salmon thrombin, despite ~390 million years of divergent evolution. The arrays also revelaed a striking change in coagulation factor Xa P2 preferences (Gly to Phe) when P1 changes from Arg to Lys. More recently, a multiplex screen across numerous proteases revealed a nM inhibitor of human cathepsin L that was a potent inhibitor of SARS coronavirus entry. While well plate technology has reached a minimum volume of ~1 microliter, microarrays break this microliter barrier for the study of nanoliter biochemical reactions.