The advent of molecular targeted agents is changing the treatment of solid tumors. In non-small-cell lung cancer, compounds
directed against oncogenic proteins offer novel therapeutic opportunities for a fraction of patients whose tumors harbor specific genetic
defects. With the increased level of resolution achieved by high-throughput technologies, the taxonomy of lung cancer is rapidly changing.
For instance, by cataloguing genetic abnormalities in squamous cell lung cancer the Cancer Genome Atlas Network revealed the existence
of multiple molecular entities, each one characterized by specific molecular abnormalities, and by a different spectrum of activated/
inactivated molecular networks. Although this increased complexity could be perceived as a further drawback in effective anticancer
therapy, on the other hand the combined interrogation of genomic and proteomic data is expected to provide the whole molecular map
of each tumor, and to determine the information flow in the explored biological system. In particular, novel genetic and proteomic approaches
are offering the opportunity for matching specific genetic defects and aberrant protein-protein interactions with active pathwaytargeted
inhibitors. Moreover, the isolation and characterization of a cellular pool endowed with stem-like traits, and able to recapitulate
the parental disease in animals, is enabling investigators to recreate the individual patient tumor in the laboratory. In this article, we discuss
how novel technologies and cellular and animal models, applied to lung cancer research, hold the potential to foster a new wave of
biomarker-driven clinical trials.