Detection of rare mutations is required for reliable identification of mutations in liquid biopsies and heterogeneous tumors. Yet low-level mutation detection remains a technically challenging task, especially when the position and type of mutation are unknown. We describe simple methods for enrichment of mutations in a sample, such that downstream detection or sequencing of mutations is facilitated. Using COLD-PCR, the sensitivity of almost all mutation detection methods is improved including targeted sequencing, digital PCR, and high resolution melting. Learning objectives include the adaptation of COLD-PCR to boost the mutation detection sensitivity for all these established platforms; and practical tips to get the most out of the combined technologies.