Saliva samples from certain disease patients harbor a wide spectrum of proteins, mRNAs, DNAs and other molecules that may be associated with the disease phenotype. If successfully discovered and validated, these informative molecules may serve as biomarkers, leading to the use of non-invasive biofluid for detecting and monitoring the diseases. This article summarizes the current advances in searching for potential biomarkers in saliva for human cancers, especially head and neck/oral cancers. With the new molecular profiling technologies such as microarray and proteomics, we are expecting to reveal highly discriminatory genomic and proteomic targets that can best detect the disease status.