Despite the dawn of the genomic information era, the challenges of cancer treatment remain formidable. Particularly for the most prevalent cancer types, including lung cancer, successful treatment of metastatic disease is rare and escalating costs for modern targeted drugs place an increasing strain on healthcare systems. Although powerful diagnostic tools to characterize individual tumor samples in great molecular detail are becoming rapidly available, the transformation of this information into therapy provides a major challenge. A fundamental difficulty is the molecular complexity of cancer cells that often causes drug resistance, but can also render tumors exquisitely sensitive to targeted agents. By using lung cancer as an example, we outline the principles that govern drug sensitivity and resistance from a genetic perspective and discuss how in vitro chemical-genetic screens can impact on patient stratification in the clinic.