The detection of micro-metastases and individual metastatic cells in lymph node tissue by spectral methods is summarized. These methods are based on instrument-based acquisition of thousands of infrared spectra of individual tissue pixels from the tissue section, and analysis of the resulting spectral hypercube by multivariate algorithms. The method of infrared image acquisition, followed by multivariate analysis, is henceforth referred to as Spectral Histopathology (SHP). SHP produces pseudo-color images of tissue sections which reveal details that compare very favorably with images collected from hematoxylin/eosin (H and E) stained tissues in that the same tissue structures are detected. However, the infrared results are based on objective and reproducible measurements and do not depend on subjective interpretation. One of the major topics of this paper is the comparison of spectral patterns observed for the same cancer type from different patients. While this is easy in some tissue types, we found it to be difficult in tissues of very different cellularity, or tissue sections that exhibit high levels of inflammatory response. In both cases, spectral quality will be compromised due to confounding effects resulting from scattering effects. The correction of these effects now permits the direct comparison of different patient samples, and paves the way for diagnostic algorithms for cancer detection to be developed.