The evolving understanding of cancer indicates every tumor has distinct characteristics driven by the molecular pathology of the disease. Predicted by this heterogeneity, targeted therapeutic agents are much more successful than a ?one size fits all? approach. Currently, there are no tools to analyze resistance in solid tissue tumor cells other than biopsy. This limitation excludes test for molecular markers that emerge during treatment. The goal of this project is to develop and characterize a CTC based molecular drug resistance test and demonstrate application in clinical samples. 15-20% of non-small cell lung cancers are driven by activating mutations in the epidermal growth factor receptor (EGFR), a mutation that can be very effectively treated with EGFR inhibitors such as gefitinib or erlotinib. Resistance to these drugs arises universally;caused half of the time by a T790M mutation. Currently, resistance is determined medically by demonstrating tumor progression. As an alternative approach, extracting the small numbers of circulating tumor cells (CTC) released into the bloodstream for detection of the emergence of the T790M mutation offers a strategy for genotyping patient-specific tumor cells in real time. This will produce a fundamentally enabling technology for predictive cancer tests in personalized medicine.