Three polymorphs of the calcimimetic cinacalcet hydrochloride were characterized by a variety of methods including thermal analysis (hot-stage microscopy and differential scanning calorimetry), vibrational spectroscopy (FT-IR and FT-Raman spectroscopy), and X-ray diffractometry (powder and single crystal). The crystal structures of all polymorphs have been determined either from single crystals (form III°) or from powder data (forms I and II). Forms III° and I both exhibit an orthorhombic cell with space group P212121, whereas form II crystallizes in the triclinic space group P1. All three polymorphs show basically the same hydrogen-bond synthon, and the structural differences are associated with conformational changes. In contrast to form III°, form II shows two conformationally different molecules, and in the high temperature form I the phenyl moiety is dynamically disordered. Among the three enantiotropically related polymorphs, form III° (Tfus: 165 °C) is the thermodynamically stable modification below the transition point of 148.5 °C, and form I (Tfus: 179.5 °C) is stable above this temperature. The phase transition between these forms is reversible, shows a hysteresis of about 30 K, and can be classified as an isosymmetric phase transition. Form II (Tfus: 170 °C) is thermodynamically unstable in the entire temperature range but shows a high kinetic stability at room temperature. Differential scanning calorimetry was identified as the most sensitive method in the evaluation of the phase purity of the polymorphs. The thermal expansion and phase transition behavior (20−170 °C) of the three forms was studied with temperature resolved powder X-ray diffraction.