There is great interest in the development of devices capable of monitoring the levels and post-translational modification states of hundreds or thousands of proteins simultaneously. One way to do this would be to create protein-detecting microarrays roughly akin to the DNA microarrays that are used for genome-wide expression studies. Two major challenges must be addressed before practical devices of this type become available. One is the development of high-throughput methods for the isolation of protein-binding compounds that will act as capture molecules in the array. The second is the optimization of methods that register binding of target proteins to the immobilized ligands in a sensitive and quantitative fashion. Progress in these areas, and some of the challenges remaining, are reviewed in this article.