The chapter discusses the immunopathology of COVID-19 and its implications for therapy. Severe COVID-19 is characterized by pneumonia, lymphopenia, exhausted lymphocytes, and a cytokine storm. While significant antibody production is observed, its role in protection or pathogenesis remains unclear. The activation of both innate and adaptive immune responses can lead to harmful tissue damage, particularly in severe cases. Patients with severe COVID-19 often exhibit lymphopenia, reduced numbers of various immune cells, and upregulated exhaustion markers. Convalescent plasma containing neutralizing antibodies has shown promise in treating severe cases, but concerns about antibody-dependent enhancement (ADE) of infection persist. Elevated levels of pro-inflammatory cytokines, such as IL-6 and IL-1β, are common in severe cases and can lead to shock and multiple organ failure. Strategies to dampen inflammatory responses, such as using IL-6 receptor-targeted monoclonal antibodies like tocilizumab, have shown initial success. Mesenchymal stem cells (MSCs) are also being explored for their anti-inflammatory and repair properties. Prognostic biomarkers and the role of chronic conditions like hypertension and diabetes in severe disease outcomes are areas of ongoing research. The combined use of anti-inflammatory and antiviral drugs, including traditional Chinese medicine, may be more effective than single modalities. Additionally, stress-induced disorders of the neuroendocrine-immune crosstalk may impact therapeutic outcomes and warrant further investigation.The chapter discusses the immunopathology of COVID-19 and its implications for therapy. Severe COVID-19 is characterized by pneumonia, lymphopenia, exhausted lymphocytes, and a cytokine storm. While significant antibody production is observed, its role in protection or pathogenesis remains unclear. The activation of both innate and adaptive immune responses can lead to harmful tissue damage, particularly in severe cases. Patients with severe COVID-19 often exhibit lymphopenia, reduced numbers of various immune cells, and upregulated exhaustion markers. Convalescent plasma containing neutralizing antibodies has shown promise in treating severe cases, but concerns about antibody-dependent enhancement (ADE) of infection persist. Elevated levels of pro-inflammatory cytokines, such as IL-6 and IL-1β, are common in severe cases and can lead to shock and multiple organ failure. Strategies to dampen inflammatory responses, such as using IL-6 receptor-targeted monoclonal antibodies like tocilizumab, have shown initial success. Mesenchymal stem cells (MSCs) are also being explored for their anti-inflammatory and repair properties. Prognostic biomarkers and the role of chronic conditions like hypertension and diabetes in severe disease outcomes are areas of ongoing research. The combined use of anti-inflammatory and antiviral drugs, including traditional Chinese medicine, may be more effective than single modalities. Additionally, stress-induced disorders of the neuroendocrine-immune crosstalk may impact therapeutic outcomes and warrant further investigation.