The determination of KRAS mutational status from tumor samples has become an important tool for patient management in colorectal and non-small-cell lung cancers. Mutations in critical areas of the gene, such as codons 12 and 13, are a negative predictor of response to anti-EGF receptor antibodies in colorectal cancer, and similarly are indicators of resistance to small-molecule tyrosine kinase inhibitors in non-small-cell lung cancer patients. A variety of laboratory methods have been developed to assess mutation status in key regions of the KRAS gene. Many of these methods, including allele-specific PCR, real-time PCR methods with melt-curve analysis, and nucleic acid sequencing techniques, provide the appropriate analytical performance to address tissue heterogeneity in tumor samples. The pathologist plays a key role in this process because assessment of morphological features of the tumor is important prior to molecular analysis. This article provides a summary of the performance characteristics of various molecular testing methods and addresses other key aspects of testing necessary to provide relevant information to help determine appropriate therapy choices.