Structure-based virtual screening can be a valuable approach to computationally select hit candidates based on their predicted interaction with a protein of interest. The recent explosion in the size of chemical libraries increases the chances of hitting high-quality compounds during virtual screening exercises but also poses new challenges as the number of chemically accessible molecules grows faster than the computing power necessary to screen them. We review here two novel approaches rapidly gaining in popularity to address this problem: machine learning-accelerated and synthon-based library screening. We summarize the results from seminal proof-of-concept studies, highlight the latest developments, and discuss limitations and future directions.