It is known that high molecular weight, thermally labile molecules can be desorbed intact using keV ion beams. This knowledge has led to numerous applications of fast atom bombardment (FAB) and secondary ion mass spectrometry (SIMS) by mass spectrometric detection of the desorbed ions. Here we show that these measurements can be significantly enhanced by using resonance enhanced laser ionization to softly ionize the neutral component of the desorbed flux. This experimental configuration can produce sensitivity improvements of several orders of magnitude over SIMS while adding a certain degree of selectivity to the ionization process itself. Examples of this performance will be presented using a wide variety of molecules including aromatic hydrocarbons, a number of biologically relevant compounds and organic polymer substrates. In some cases, detection limits in the attomole range can be achieved.