Human saliva contains proteins that can be informative for disease detection and surveillance of oral health. Comprehensive analysis and identification of the proteomic content in human whole and ductal saliva is a necessary first step toward the discovery of saliva protein markers for human disease detection. The article will review the recent advances in human saliva proteome analysis, including the efforts of the UCLA saliva proteome consortium funded by the National Institute of Dental and Craniofacial Research (NIDCR). We aim to summarize the proteomics technologies currently used for global analysis of saliva proteins and to elaborate on the application of saliva proteomics to discovery of disease biomarkers, in particular for oral cancer and Sjögren's syndrome, and discuss some of the critical challenges and perspectives for this emerging field. The impact of human saliva proteome analysis in the search for clinically relevant disease biomarkers will be realized through advances made using proteomics technologies.