Fragment-like natural products play a pivotal role in natural product research given their improved synthetic and computational tractability as well as commercial availability compared to more complex natural product structures. A multitude of computational tools have been developed to support the generation, analysis, and application of natural fragments for drug discovery and chemical biology research. In this contribution, the challenges and opportunities in such workflows are discussed and contextualized. Multiple successful applications and validations discussed herein attest to the relevance of natural fragments for drug discovery and the utility of machine learning and data science to support such endeavors.