The lead generation phase is the stage in early drug discovery that refers to the process of identifying hit molecules that interact with the desired target, followed by a limited optimisation of those hits. During this period the project aims to identify high-quality chemical tools suitable for advanced cellular and in vivo studies which will help to strengthen the validation of the target and increase confidence in the proposed therapeutic hypothesis. This chapter gives an overview of the major hit finding approaches together with their strengths and limitations. The process of hit profiling and hit selection, as well as hit expansion, are illustrated, and complications that can be encountered during this initial phase are highlighted. The advantage of using an integrated lead generation strategy is emphasised. A well-defined lead generation strategy, where two or more complementary hit finding approaches are executed in parallel, combined with a screening cascade containing relevant biological assays, will often result in the identification of structurally diverse lead series, leading ultimately to successful clinical candidates.