Genome editing with programmable nucleases, such as CRISPR-Cas, has ushered in a new era of personalized medicine. In recent years, several approaches for the treatment of congenital and acquired diseases have been developed and successfully transferred into clinical trials. The first CRISPR-based drugs for hemoglobinopathies are expected to be approved in Europe this year. In my talk, I will briefly introduce the principles of genome and base editing, present some examples of successfully applied editing strategies, and conclude my talk with lessons we learnt from assessing off-target effects in clinically relevant cell types, enabling us to assess the risk of genotoxicity and to improve the safety of these new therapeutic approaches.