Availability of large volumes of genomic and enzymatic data for taxonomically and phenotypically diverse organisms allows for exploration of the adaptive mechanisms that led to diversification of enzymatic functions. We present an algorithmic approach and a computational framework, Chisel, for automated and interactive identification, comparative analysis, and characterization of evolutionary variations of enzymes. Chisel contains over 8,500 clusters and subsequent computational models specific for 939 distinct enzymatic functions and, when data is sufficient, their taxonomic variations.