Laser-induced fluorescence spectroscopy is a promising technique for detecting colonic dysplasia in vivo but, at present, the biological basis for the success of the method is poorly understood, and little information is provided as to the morphological/molecular origin of tissue fluorescence. We present a methodology for establishing this, taking as a starting point a recently completed prospective LIF clinical study of colonic polyps. The method is based on a morphological model of tissue fluorescence with three components: the intrinsic lineshapes of the fluorophores, the spatial distributions of their intensities, and the optical parameters of tissue. We measure these using fluorescence microspectroscopy, microscopic imaging and tissue optics, respectively. The model predicts the features of the clinical spectra, and quantifies the respective intrinsic and architectural contributions. The results can be inverted to extract biological parameters from the spectra, and used to select optimal excitation wavelength(s) and guide probe design. Implications for the detection of non-polypoid dysplasia are discussed.