Abstract Over the past three decades, significant advancements have been made in mutation enrichment methods, driven by the increasing need for precise and efficient identification of rare genetic variants associated with diseases. Mutation‐enrichment methods have emerged to boost sensitivity and enable easy detection of low‐frequency mutations. These methods are crucial in genomics research and clinical diagnostics, allowing for the detection of low‐frequency mutations within large genomic datasets. This review presents a summary of technological developments in rare mutation enrichment and emphasizes their mechanisms and applications in liquid biopsies.