Antibodies are by far the most versatile, valuable, and widely used protein-binding agents. They are essential tools in biological research and are increasingly being developed as therapeutic reagents. However, antibodies have a number of practical limitations, and it would be desirable in many applications to replace them with simpler, more robust synthetic molecules. Unfortunately, synthetic protein-binding agents rarely exhibit the high affinity and specificity typical of a good antibody. This article reviews efforts to overcome these limitations and to develop a facile, high-throughput methodology for the isolation of synthetic protein ligands with antibody-like binding characteristics.