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The global response to the COVID-19 pandemic has necessitated a fine balance between therapeutic efficacy and minimizing adverse effects, including thrombotic events and systemic complications associated with SARS-CoV-2. This chapter explores the multifaceted nature of COVID-19 pathophysiology, highlighting key mechanisms such as hypercoagulability, cytokine storm syndromes, and endothelial dysfunction that contribute to disease severity. Global insights have informed risk stratification and mitigation strategies, integrating anticoagulation therapies, immunomodulatory approaches, and precision medicine. By emphasizing a comprehensive framework for risk-benefit analysis, this work underscores the critical importance of individualized treatment protocols and adaptive clinical guidelines to ensure patient safety and optimize therapeutic outcomes in the ongoing fight against SARS-CoV-2. The emergence of SARS-CoV-2, the virus responsible for COVID-19, brought an unprecedented response from the scientific community. Unlike past outbreaks, SARSCoV-2 had a rapid global spread, leading to wide-reaching consequences on health, economies, and societies. As a result, the pace of research and therapeutic development was significantly accelerated, with scientists worldwide collaborating to understand the virus’s biology, transmission patterns, and potential treatment methods. The key areas of focus included antivirals, vaccines, monoclonal antibodies, and supportive therapies to address COVID-19’s various symptoms and complications. This chapter provides a comprehensive examination of the dual challenges of maximizing therapeutic benefit while minimizing harm in COVID-19 treatment. Drawing on global insights and evidence from clinical trials, it highlights the importance of precision medicine approaches, individualized risk stratification, and adaptive clinical frameworks. As the world transitions from pandemic response to long-term management of SARS-CoV-2 and its complications, the lessons learned from balancing efficacy and safety will be essential for addressing not only COVID-19 but also future global health crises.