The series of phase transitions on increasing pressure and on reverse decompression was followed in crystals of monoclinic and orthorhombic polymorphs of L-cysteine by using Raman spectroscopy, with the samples placed in a diamond anvil cell together to ensure identical pressures on the two samples. The effects of hydrostatic pressure on the two polymorphs are shown to be radically different. Depending on the starting polymorph, different phases are formed under identical compression/decompression conditions. The effect of pressure on the monoclinic polymorph was studied for the first time. Phase transitions in monoclinic L-cysteine (at ∼2.9 and ∼3.9 GPa) are completely reversible without a noticeable hysteresis. The changes in the spectra suggest that the H-bond network is distorted and SH···O bonding dominates over SH···S bonding at high pressures, but the molecular conformations change continuously during these transitions. The data on the orthorhombic polymorph of L-cysteine show that not only the H-bond network is distorted, but also the conformation of the L-cysteine zwitterion changes very substantially. The previously observed discrepancy in the results related to the occurrence of a phase existing between 2.1 and 2.3 GPa reported by Minkov et al. (J. Phys. Chem. B. 2008; 112, 8851) but not observed by Moggach et al. (Acta Crystallogr. B. 2006; 62, 296) could be interpreted; different phases can be formed at the same pressure, depending on how this pressure was reached: on direct compression, or in the compression–decompression–compression cycle. Copyright © 2010 John Wiley & Sons, Ltd.