Machine-guided capsid engineering represents a new approach to overcome the current challenges of in vivo gene delivery. Such an approach combines three advanced technologies: i. next-gen library synthesis, ii. next-gen sequencing, and iii. machine learning. With this workflow the search for improved capsids can be dramatically accelerated. This talk will review the technological advances that are pushing the field of AAV capsid engineering toward machine-guided methods, describe and explore the promise of this new approach, and discuss anticipated challenges. In the near future, machine-guided methods will revolutionize our ability to design robustly efficient, safe and targeted vectors for the treatment of genetic conditions.