In this article, we discuss some aspects of the combined quantum mechanics/molecular mechanics (QM/MM) method for the calculation of energetics and spectroscopic parameters of protein‐bound cofactors. Following a brief introduction to the theory of the QM/MM approach, some selected examples are discussed that illustrate the use of this methodology in theoretical spectroscopic studies. The examples cover the following: (i) excitation energies for the
S
0
→
S
1
transition in bacteriorhodopsin; (ii) electron paramagnetic resonance (EPR) and absorption spectra of plastocyanin; and (iii) the spin Hamiltonian parameters of compound I in cytochrome
P
450
cam
.