Many light-induced molecular processes involve a change in spin state and are formally forbidden in non-relativistic quantum theory. To make them happen, spin–orbit coupling (SOC) has to be invoked. Intersystem crossing (ISC), the nonradiative transition between two electronic states of different multiplicity, plays a key role in photochemistry and photophysics with a broad range of applications including molecular photonics, biological photosensors, photodynamic therapy, and materials science. Quantum chemistry has become a valuable tool for gaining detailed insight into the mechanisms of ISC. After a short introduction highlighting the importance of ISC and a brief description of the relativistic origins of SOC, this article focusses on approximate SOC operators for practical use in molecular applications and reviews state-of-the-art theoretical methods for evaluating ISC rates. Finally, a few sample applications are discussed that underline the necessity of studying the mechanisms of ISC processes beyond qualitative rules such as the El-Sayed rules and the energy gap law. © 2011 John Wiley & Sons, Ltd.