The isolation and identification of new and novel natural products is a challenging task; one that requires the separation of a single component from hundreds of others like it. The development of a suitable dereplication and metabolic fingerprinting technique early in the isolation workflow is therefore crucial for successful natural product-based drug discovery programmes. Herein, we present an approach based on 1H NMR analysis of a library of lead-like enhanced fractions. Examples of new natural products sourced from marine sponges and microbes as well as bioactive compounds identified from high-throughput screens using this methodology will be presented.