Important advances in lung cancer treatment have been made over the last decade. Several drugs designed to target molecular pathways involved in cancer-cell growth and survival have been shown to be effective in a selected fraction (<20%) of non-small cell lung cancer patients. Somatic mutations in several genes (i.e.: EGFR and KRAS) can predict patient's response to targeted therapies. Those mutations are commonly detected on histopathological samples (core-needle biopsy/ surgical resection). However, when tissue biopsies are not available, molecular testing has to be performed on cytological specimens. Issues raised by molecular testing on cytological specimen are discussed in this article.