Introduction to Semirational Protein Design Protein design tools have become very diverse. As a combination of rational design and directed evolution, semi-rational protein design has been developed to address the limitations of both methods. Information on protein sequence, structure and function is used together with predictive algorithms to identify target amino acid residues. The methodological advances in semirational protein design provide synthetic biology with more powerful and effective strategies. These combinatorial methods have successfully enabled existing proteins to repurpose to adopt new functions.