While prevention is a bedrock of public health, innovative therapeutics are needed to complement the armamentarium of interventions required to achieve disease control and elimination targets for neglected diseases. Extraordinary advances in drug discovery technologies have occurred over the past decades, along with accumulation of scientific knowledge and experience in pharmacological and clinical sciences that are transforming many aspects of drug R&D across disciplines. We reflect on how these advances have propelled drug discovery for parasitic infections, focusing on malaria, kinetoplastid diseases, and cryptosporidiosis. We also discuss challenges and research priorities to accelerate discovery and development of urgently needed novel antiparasitic drugs.