The objective of this study was exploration of the potential, offered by the laser microprobe mass spectrometer (LAMMA), for the in situ localization of organic targets in embedded tissues by means of structurally relevant ions. A series of model systems was designed to evaluate stepwise the analytical problems involved. A preliminary screening pointed to the position of the target in comparison to the actual sample surface as a determining parameter. Refined simulations were carried out with sandwich samples, consisting of an epon carrier (thickness 1 micron), coated with microcrystalline targets and covered with a layer between 5 and 50 nm of different materials (epon, carbon, formvar). In addition to the stimulated conversion of molecular into fragment ions, the presence of a barrier leads to a drastic loss of sensitivity (20-50 x) and unacceptable degradation of the mass spectrometric quality (resolution, calibration).