The solvent formation of phenobarbital, an important drug compound with an unusually complex polymorphic behavior, was studied in detail. Monosolvates with acetonitrile, nitromethane, dichloromethane, and 1,4-dioxane were produced and characterized by single-crystal and powder X-ray diffraction, thermoanalytical methods, FT-IR, Raman, and solid-state NMR spectroscopy. Thermal desolvation of these compounds yields mainly mixtures of polymorphs III, II, and I. At a low relative humidity (25 °C) the solvates transform to polymorph III, and at higher relative humidity the monohydrate and the metastable polymorphs IV and VI can be present as additional desolvation products. These results highlight the potential complexity of desolvation reactions and illustrate that a tight control of ambient conditions is a prerequisite for the production of phase-pure raw materials of drug compounds. Transformation in aqueous media results in the monohydrate. Below room temperature, the 1,4-dioxane monosolvate undergoes a reversible single-crystal-to-single-crystal phase transition due to the ordering/disordering of 50% of its solvent molecules. Dipolar-dephasing NMR experiments show that the solvent molecules are relatively mobile. Deuterium NMR spectra reinforce that conclusion for the dioxane solvent molecules. The crystal structure of an elusive 1,4-dioxane hemisolvate was also determined. This study clearly indicates the existence of "transient solvates" of phenobarbital. The formation of unstable phases of this kind must be considered in order to better understand how different solvents affect the crystallization of specific polymorphs.