Hit generation is a crucial step in drug discovery that will determine the speed and chance of success of identifying drug candidates. Many strategies are now available to identify chemical starting points, or hits, and each biological target warrants a tailored approach. In this set of best practices, we detail the essential approaches for target centric hit generation and the opportunities and challenges they come with. We then provide guidance on how to validate hits to ensure medicinal chemistry is only performed on compounds and scaffolds that engage the target of interest and have the desired mode of action. Finally, we discuss the design of integrated hit generation strategies that combine several approaches to maximize the chance of identifying high quality starting points to ensure a successful drug discovery campaign.