Restriction endonucleases are among the most accurate enzymes known (Pingoud and Jeltsch 2001). Consequently, changing their very high sequence specificity is one of the scientific goals in studying these enzymes (Jeltsch et al. 1996). This review focuses on protein engineering regarding Type II restriction enzymes. They comprise the vast majority of the about 3600 entities listed in REBASE today (Roberts et al. 2003), although the number of those studied in detail is far smaller.