Abstract: The object of proteomics is the performer of our lives—protein, while the malignant pleural effusion contain abundant protein, especially tissue-specific protein and disease-related protein. Proteomic investigation on malignant pleural effusion is of great significance in recognizing its protein profile, exploring new disease-related biomarkers and finding pathogenesis. In this review we will summarize recent advance in proteomic investigation of pleural effusion on two aspects, knowledge-based proteomics and comparative proteomics.