Protein and heme structural changes of ferric and ferrous cytochrome c (Cyt-c) that are induced by electrostatic binding (e.g., liposomes, electrodes), by hydrophobic interactions (e.g., monomeric sodium dodecyl sulfate), by guanidium hydrochloride (GuHCl), and at low pH and high temperature were studied by UV-vis absorption, circular dichroism (CD), electron paramagnetic resonance (EPR), and (surface-enhanced) resonance Raman [(SE)RR] spectroscopy. In a global spectral analysis, all species that differ with respect to the heme structure were identified and characterized in terms of the spin and ligation state of the heme as well as of protein secondary and tertiary structure changes. The results indicate that the upper part of the heme pocket including the Met-80 ligand is the most labile protein region such that this ligand is dissociated from the heme iron in all normative Cyt-c states. Among these states, there are two six-coordinated low-spin (LS) configurations with H2O or His-33 serving as the sixth (axial) ligand. Whereas the ferric H2O/His-18-ligated low-spin species is only formed in the A state at low pH and high ionic strength, the His-33/His-18-ligation pattern corresponds to a stable ferric configuration inasmuch as it can be induced by electrostatic and hydrophobic interactions and under nondenaturing and denaturing conditions, that is, nearly independent of the secondary structure. Conversely, the heme pocket on the opposite side of the heme remains largely preserved except for ferric Cyt-c at very low pH and high GuHCl concentrations as indicated by the replacement of His-18 by a water molecule. Structural changes that are localized in the heme pocket and lead to a ferric bis-His-coordinated LS, a ferric water/His and mono-His high-spin (HS), and a ferrous mono-His HS configuration may be induced by hydrophobic or electrostatic interactions with the front surface of Cyt-c. The present study contributes to a consistent description of the conformational manifold of Cyt-c, which is essential for elucidating the role of conformational transitions during the natural functions of Cyt-c in energy transduction and apoptosis.