The simple catalytic motifs utilized by enzymes created by computational design and directed evolution constitute a potentially valuable source of chemical promiscuity, Here we show that the artificial retro-aldolase RA95.5-8 is able to use a reactive lysine in a hydrophobic pocket to accelerate promiscuous Knoevenagel condensations of electron-rich aldehydes and activated methylene donors. Optimization of this activity by directed evolution afforded an efficient enzyme variant with a catalytic proficiency of 5 X 10(11) M-1 and a >10(8)-fold catalytic advantage over simple primary and secondary amines. Divergent evolution of de novo enzymes in this way could be a promising, strategy for creating tailored biocatalysts for many synthetically useful reactions.