Artificial metalloenzymes have been recently established as efficient alternatives to traditional transition metal catalysts. The presence of a secondary coordination sphere in artificial metalloenzymes makes them advantageous over transition metal catalysts, which rely essentially on their first coordination sphere to exhibit their catalytic activity. Recent developments on streptavidin- and avidin-based artificial metalloenzymes have made them highly chemically and genetically evolved for selective organometallic transformations. In this review, we discuss the chemo-genetic optimization of streptavidin- and avidin-based artificial metalloenzymes for the enhancement of their catalytic activities towards a wide range of synthetic transformations. Considering the high impact in vivo applications of artificial metalloenzymes, their catalytic efficacies to promote abiological reactions in intracellular as well as periplasmic environment are also discussed. Overall, this review can provide an insight to readers regarding the design and systematic optimization of strept(avidin)-based artificial metalloenzymes for specific reactions. This journal is © 2020 The Royal Society of Chemistry.