Aspects of the present invention relate to a method for the preparation of samples for MALDI MS imaging. Certain embodiments relate to a method of matrix deposition for samples, wherein tissue sections are prepared via a synergistic combination of fixation with matrix. In certain embodiments, tissue is fixed with cold solvent, according to well-established histology protocols, and in the presence of matrix, allowing for high resolution spatial mapping of protein, lipid, sugar, and/or nucleic acid distribution. In certain embodiments, the present invention relates to fixation with matrix of whole organisms. In certain embodiments, animals are perfused with fixation and matrix mixtures, which allows for direct mass spectrometry analysis.