Depending on crystallization conditions many organic compounds can form crystals of different structure. Their proper characterization is important, for example, in pharmaceutical industry. While the x-ray diffractometry established as a standard method, alternative techniques are desirable for broader application flexibility and economic reasons. In the present study, Raman spectroscopy combined with the density functional calculations is suggested as a complementary method to the x-ray and other higher-resolution techniques. The potential to discriminate structural differences in polymorphic crystalline forms is documented on three model compounds of industrial importance. Methacrylamide, piracetam, and 2-thiobarbituric acid were crystallized under various conditions, and their Raman spectra recorded using 532 nm and 1064 nm laser excitations. X-ray diffractometry and nuclear magnetic resonance spectroscopy were used as complementary techniques to verify sample composition and structure. To interpret the observed differences in Raman frequencies and intensities three computational strategies were explored, based on single molecule, a cluster model, and a plane-wave periodic boundary conditions calculation. The single-molecule modeling was found inadequate, whereas the plane-wave approach provides the most realistic spectra. For all compounds, the differences in the Raman spectra of polymorphic forms could be unambiguously assigned to the simulations. The modeling revealed that the spectral differences were caused by the molecular structure itself as well as by crystal packing. The relative importance of these factors significantly varied across the investigated samples. Owing to its simplicity the Raman spectroscopy appears to be a promising technique capable of reliable discriminating between organic crystal polymorphic states.