Drug-discovery and drug-development endeavors are laborious, costly and time consuming. These programs can take upward of 12 years and cost US $2.5 billion, with a failure rate of more than 90%. Machine learning (ML) presents an opportunity to improve the drug-discovery process. Indeed, with the growing abundance of public and private large-scale biological and chemical datasets, ML techniques are becoming well positioned as useful tools that can augment the traditional drug-development process. In this Perspective, we discuss the integration of algorithmic methods throughout the preclinical phases of drug discovery. Specifically, we highlight an array of ML-based efforts, across diverse disease areas, to accelerate initial hit discovery, mechanism-of-action (MOA) elucidation and chemical property optimization. With advances in the application of ML across diverse therapeutic areas, we posit that fully ML-integrated drug-discovery pipelines will define the future of drug-development programs.