Epithelial cells play an important role in physiological and pathophysiological situations, with organ-, tissue-, type-, and function-specific patterns. Proteome analysis has been used to study epithelial-origin diseases and identify novel prognostic, diagnostic, and therapeutic markers. The present review compares the variation of sample preparation for epithelial proteomic analysis, search similarities, and differences of epithelial proteomics between different cells, locations, and diseases. We focus on specificity of proteomic markers for epithelial-involved diseases. Proteomic alterations in epithelial cell lines were mapped to understand protein patterns, differentiation, oncogenesis, and pathogenesis of epithelial-origin diseases. Changes of proteomic patterns depend on different epithelial cell lines, challenges, and preparation. Epithelial protein profiles associated with intracellular locations and protein function. Epithelial proteomics has been greatly developed to link clinical questions, e.g., disease severity, biomarkers for disease diagnosis, and drug targets. There is an exciting and attractive start to link epithelial proteomics with histology of clinical samples. From the present review, we can find that most of disease-associated investigation of epithelial proteomics has been focused on epithelial-origin cancer. There is a significant gap of epithelial proteomics between acute and chronic organ injury, inflammation, and multiple organ dysfunction. Epithelial proteomics will provide powerful information on the relationships between biological molecules and disease mechanisms. Epithelial proteomics strategies and approaches should become more global, multidimensional, and systemic.