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Oral cancer is one of the significant global health concerns with reports of more than ten million new cases and mortality of six million, each year. The current clinical procedure for oral cancer detection is visual examination followed by histopathological analysis of biopsied lesion. However, this procedure often leads to multiple biopsies due to the difficulty in identifying the most malignant site for biopsy and that the procedure is invasive and time-consuming in nature. This book presents an overview of non-invasive and real-time diagnostic techniques based on tissue fluorescence and diffuse reflectance to detect oral cancer using both point monitoring and multi-spectral imaging. The clinical study results of diffuse reflectance spectral imaging at oxygenated hemoglobin absorption dips establish the potential of this imaging modality in detecting squamous cell carcinoma affecting epithelial tissues of various organs and for biopsy guidance. The ability to observe disease onset and progression through non-invasive and cost effective screening methods at the population level would help to implement prevention and treatment strategies at an early stage.