Many enzymes possess high catalytic efficiency and selectivity that far surpass classical organic or organometallic catalysts. However, the initial starting enzyme for a given transformation does not always possess the right properties needed for broad utilization. Searching in genome/protein sequence libraries for homologs, aided with powerful bioinformatic tools developed in recent years, provides an avenue to identify superior biocatalysts. Herein, we highlight several case studies to illustrate the power of this concept. A brief discussion on its complementarity with contemporary approaches in protein engineering (such as directed evolution) and possible future developments is also provided.