Lung cancer (specifically, non-small cell lung cancer; NSCLC) is the leading cause of cancer-related deaths in the United States. Poor response rates and survival with current treatments clearly indicate the urgent need to develop an effective means to treat NSCLC. Magnetic hyperthermia is a novel non-invasive approach for ablation of lung tumors, and is based on heat generation by magnetic materials, such as superparamagnetic iron oxide (SPIO) nanoparticles, when subjected to an alternating magnetic field. However, inadequate delivery of magnetic nanoparticles to tumor cells can result in sub-lethal temperature change and induce resistance. Additionally, non-targeted delivery of these particles to the healthy tissues can result in toxicity. To overcome these problems, we used aerosol-based, tumor-targeted SPIO nanoparticles to induce highly selective hyperthermia for the treatment of lung cancer.Mechanistic study on the mode of cell kill by magnetic hyperthermia revealed that the extent and mechanism of MH-induced cell kill is dramatically altered with aggregation of SPIO nanoparticles. While well-dispersed SPIO nanoparticles induced apoptosis similar to that observed with conventional hyperthermia, sub-micron size aggregates, induced temperature-dependent autophagy through generation of oxidative stress. Micron size aggregates caused rapid membrane damage and acute cell kill, likely due to physical motion of the aggregates in alternating magnetic field. Overall, this work highlighted the potential for developing highly effective anticancer therapeutics through designed aggregation of SPIO nanoparticles. Cancer stem cells (CSCs) are a sub-population of stem-like cells that are thought to be responsible for tumor drug resistance and relapse. We determined the susceptibility of CSCs to magnetic hyperthermia. Multiple assays for CSCs, including side population phenotype, aldehyde dehydrogenase expression, mammosphere formation and in vivo xenotransplantation, indicated that magnetic hyperthermia reduced or, in some cases, eliminated the CSC sub-population in treated cells. Magnetic hyperthermia demonstrated pleiotropic effects, inducing acute necrosis in some cells while stimulating reactive oxygen species generation and slower cell kill in others. These results suggest the potential for lower rates of tumor recurrence after magnetic hyperthermia compared to conventional cancer therapies. We then studied the effectiveness of inhalation delivery of tumor targeted SPIO nanoparticles for magnetic hyperthermia treatment of lung cancer. We developed EGFR-targeted, inhalable SPIO nanoparticles for magnetic hyperthermia of NSCLC. EGFR targeting resulted in 50% higher concentration of iron oxide in the lungs 1 week post inhalation, when compared to non-targeted SPIO nanoparticles. Magnetic hyperthermia using targeted SPIO nanoparticles resulted in significant inhibition of in vivo tumor growth over a period of one month. Overall, this work demonstrates the potential for developing an effective anticancer treatment modality for the treatment of NSCLC, using targeted magnetic hyperthermia.