Faced with a protein engineering challenge, a contemporary researcher can choose from myriad design strategies. Library-scale computational protein design (LCPD) is a hybrid method suitable for the engineering of improved protein variants with diverse sequences. This chapter discusses the background and merits of several practical LCPD techniques. First, LCPD methods suitable for delocalized protein design are presented in the context of example design calculations for cellobiohydrolase II. Second, localized design methods are discussed in the context of an example design calculation intended to shift the substrate specificity of a ketol-acid reductoisomerase Rossmann domain from NADPH to NADH.