Mutation scanning techniques are used to detect sequence variants without the need for prior knowledge of the identity or precise location of the variant, in contrast with genotyping techniques, which determine the status of a specific variant. High-resolution melting is a recently developed method that shows great potential as a mutation scanning technique. Sensitivity and specificity for mutation detection are extremely high and the technique also has advantages of cost and throughput. Practical considerations for successful mutation scanning by high-resolution melting are also discussed in this review.