Cancer kills more Americans under the age of 75 than any other disease. Although most cancers occur in epithelial surfaces that can be directly visualized, the majority of cases are detected at an advanced stage. Optical imaging and spectroscopy may provide a solution to the need for non-invasive and effective early detection tools. These technologies are capable of examining tissue over a wide range of spatial scales, with widefield macroscopic imaging typically spanning several square-centimeters, and high resolution in vivo microscopy techniques enabling cellular and subcellular features to be visualized. This work presents novel technologies in two important areas of optical imaging: high resolution imaging and widefield imaging. For subcellular imaging applications, new high resolution endomicroscope techniques are presented with improved lateral resolution, larger field-of-view, increased contrast, decreased background signal, and reduced cost compared to existing devices. A new widefield optical technology called multi-modal spectral imaging is also developed. This technique provides real-time in vivo spectral data over a large field-of-view, which is useful for detecting biochemical alterations associated with neoplasia. The described devices are compared to existing technologies, tested using ex vivo tissue specimens, and evaluated for diagnostic potential in a multi-patient oral cancer clinical trial.