The discovery of targetable driver mutations in pulmonary adenocarcinoma has revolutionized the field of thoracic oncology by the introduction of oral small molecule tyrosine kinase inhibitors that target specific EGFR mutations and EML-4/ALK rearrangement. Therefore, testing for EGFR gene mutations and ALK rearrangements has become part of everyday clinical practice. The majority of lung cancer patients present at an advanced stage, where small biopsy and cytology specimens are often the only available material for diagnostic workup and molecular characterization. Mutation testing has become the standard of care. Nonetheless, the technical complexity and relative high cost of the test have challenged the widespread use of molecular techniques in everyday clinical settings. Recently, antibodies to specific molecular alterations have become available and have the potential to become instruments for the molecular characterization of tumors. In this review article we will discuss practical issues in molecular characterization of lung adenocarcinoma on cytology material and the use of immunocytochemical stains for the detection of mutant protein as an alternative or adjunct to molecular techniques.