Human saliva holds tremendous potential for transforming disease and health diagnostics given its richness of molecular information and non-invasive collection. Enumerating its molecular constituents is an important first step towards reaching this potential. Among the molecules in saliva, proteins and peptides arguably have the most value: they can directly indicate biochemical functions linked to a health condition/disease state, and they are attractive targets for biomarker assay development. However, cataloging and defining the human salivary proteome is challenging given the dynamic, chemically heterogeneous and complex nature of the system. In addition, the overall human saliva proteome is composed of several “sub-proteomes” which include: intact full length proteins, proteins carrying post-translational modifications (PTMs), low molecular weight peptides, and the metaproteome, derived from protein products from nonhuman organisms (e.g. microbes) present in the oral cavity. Presented here will be a summary of communal efforts to meet the challenge of characterizing the multifaceted saliva proteome, focusing on the use of mass spectrometry as the proteomic technology of choice. Implications of these efforts to characterize the salivary proteome in the context of disease diagnostics will also be discussed.