The development of enzymes or antibodies that fulfill specific economic needs is a key technology for Flanders’ vibrant biotech sector. Unfortunately, today’s strategies for directed protein evolution do not make use of the full range of mutation types that contribute to functional innovation in Nature. Protein engineers are traditionally focused on amino acid substitutions. Meanwhile, insertions and deletions (indels) rarely receive any attention at all, despite being one of the most common sources of genetic variation. Although our understanding of indels is still in its infancy, it is clear that they can exert a great influence on the properties of a protein, for better or for worse. In this project, I will develop powerful indel-centered protein engineering strategies and study the effects of these understudied mutations at the molecular level. Furthermore, my efforts will not be limited to in-frame indels. The potential of the intriguing frameshifting indels that drastically modify the downstream sequence will be evaluated as well. I anticipate that these insights will expand not only our protein engineering toolbox, but also our view of natural protein evolution.