Receptor tyrosine kinases (RTKs) are integral membrane proteins that belong to the family of cell surface receptors. Recent studies on RTKs have uncovered their multifaceted roles in both normal and pathological processes, particularly in the context of cancer. Under normal physiological conditions, RTKs are essential for orchestrating fundamental cellular functions, such as tissue repair and organ morphogenesis, enabling proper development and maintenance of cellular functions. However, during oncogenesis, they facilitate cell motility, invasion, and tumor angiogenesis, ultimately leading to uncontrolled cell proliferation, tumor progression, and metastasis. This comprehensive chapter discusses the intricate biology of RTKs, encompassing their structural features, signaling mechanisms, and significant roles in cancer progression and therapy resistance. We highlighted the complex networks of the most prevalent RTK subfamilies—including ErbB, PDGFR, VEGFR, FGFR, and HGFR, highlighting their critical contributions to cancer development and treatment challenges. Furthermore, we examine the transformative impact of RTK-targeted therapies, specifically small molecule kinase inhibitors that have revolutionized cancer treatment. These therapies improve patient outcomes by precisely targeting the mechanisms driving cancer. However, we also acknowledge the enduring challenges of drug resistance and the critical need for personalized therapeutic approaches to overcome these hurdles and ensure long-term effectiveness.