Several techniques have been used to increase the possible sequences that can be explored by combinatorial methods. As point mutations lead to rather conservative changes and limited sampling of the available sequence space, it is desirable to also explore those sequences that are accessible by two or three base substitutions in a single codon. A codon-level combinatorial method that enables all possible replacements to be made at any given position has been used to mutate six contiguous residues of β -lactamase, and this led to the selection of a ceftazidimeresistant triple mutant deletion mutagenesis (RID). Random insertion/ mimics other evolutionary processes that are difficult to simulate by PCR methods.