Organ dysfunction is defined as a systemic consequence of acute and chronic diseases, a critical and important phase of disease development. The mortality of patients with severe illness is highly correlated with the number and duration of dysfunctional organs. There is still not an efficient and specific therapy to improve the prognosis of patients with organ dysfunction, due to the complexity and severity of the disease. There is a great need to understand molecular mechanisms of the disease, identify disease-related biomarkers, and validate therapeutic effects. Thus, it is important to have a special attention from proteomic scientists to explore the combination between advanced proteomic biotechnology, clinical proteomics, tissue imaging and profiling, and organ dysfunction score systems, to improve the clinical outcomes of these patients.