Tumors emerge due to somatic mutations that result in biological advantages for the transformed cells. Such mutations are generally known as ‘drivers’ and can be classified into two groups: (i) ‘loss-of-function’ mutations, which inactivate tumor suppressor genes and (ii) ‘activating’ or ‘gain-of-function’ mutations that convert proto-oncogenes to oncogenes. Of particular relevance are activating mutations in protein kinase (PKs) genes —such as EGFR, HER2 or BRAF— which constitute driver events in many human tumor types and correlate with good responses to new generations of antitumor drugs that are kinase inhibitors. With the advent of Next Generation Sequencing (NGS) technologies, thousands of changes in DNA are being detected through the genomic sequencing of human malignancies, and mutations either new or not functionally characterized are often found. In particular, many of the single nucleotide variations in PK genes are likely to be passenger mutations or even polymorphisms. Discriminating driver mutations in PKs that correlate to sensitivity to kinase inhibitors is a significant challenge that should be faced in a multidisciplinary manner. Molecular tumor boards that integrate oncologists, pathologists and molecular biologists constitute a good option to perform this “functional annotation” of the mutations found by NGS.