Non-small cell lung cancer is possibly the solid tumor with more potential drugable molecular targets, but the smallest tumor specimens. An optimization of tumor tissue handling is then mandatory. In this landscape, the precise definition of non-small cell lung cancer histologic type had a renewal role in selecting different therapeutic strategies, also leading to a large use of immunohistochemistry even in malignancies showing an overt morphologic differentiation. We suggest here 4 different clinicopathologic scenarios with some helpful rules aimed at preventing unnecessary and expensive immunostains, then underlining the ageless value of morphology and preserving tumor tissues for molecular investigations.