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Objectives: Treatment of patients with non-small cell lung cancer continues to evolve and the discovery and approval of tyrosine kinase inhibitors in patients with NSCLC and targetable alterations brought an important contribution in treating these patients. Material and Methods: This review aims to describe the main alterations that can affect the signaling pathways involved in NSCLC, present the therapy that can target these alterations and describe the mechanisms that can determine resistance to targeted therapy. Literature research was performed on PubMed and Google Scholar and 60 relevant articles were selected for the purpose of our review. Discussion: The data of the present research were structured in nine paragraphs, each one presenting the main alterations that can affect the signaling pathways in patients diagnosed with NSCLC, targeted therapy used in managing these cases and mechanisms of resistance to targeted therapy. Conclusions: Testing for molecular biomarkers should be mandatory for every newly diagnosed NSCLC patient in order to offer the most appropriate treatment.