Genetic aberrations that cause constitutive activation of the receptor tyrosine kinase (RTK), ROS1, can drive cancer formation. Treatment of these cancers with tyrosine kinase inhibitors (TKIs) can lead to cancer reduction in patients. While ROS1-TKIs have achieved notable success in the clinic, especially in the treatment of non-small-cell lung cancer (NSCLC), patients eventually stop responding to treatment, as seen with other forms of targeted therapy. Therapeutic resistance represents a formidable challenge to overcome as secondary alterations either in ROS1 itself or in alternative proto-oncogenes and tumor-suppressors can reduce TKI efficacy. Furthermore, we still have a rudimentary understanding of the spectrum of ROS1-independent alterations that can cause therapeutic resistance. In addition to combating resistance, an outstanding question exists as to if single point mutations in ROS1 can promote constitutive activation of the receptor like what is observed with other RTKs. If so, a need would also exist to test the efficacy of ROS1-TKIs against these alterations. Research presented in this dissertation attempts to address these unmet clinical and research needs.