The use of CRISPR-derived, RNA-guided nucleases for genome editing has shown great promise for addressing genetic disease. Encouraging work in cell culture and animal models has demonstrated the capability of genome-editing enzymes to correct disease-causing loci, but clinical translation can only proceed once the corrective enzymes have been rendered safe, effective, and capable of being delivered to the appropriate cells. To address these needs, there has been rapid and extensive progress in the engineering of the RNA and protein components of Cas9, the most widely-used genome editor. Here we review advances in engineering of the enzyme Cas9 by altering its chemical or molecular composition. Such efforts have enhanced enzyme stability, improved capacity for delivery, augmented specificity, and broadened the horizons of genome manipulation.