Hardware-in-the-loop (HIL) simulation is today an integral part in the vehicle development process as a method for testing electronic control unit (ECU) software. HIL simulation is used for all aspects of development, naturally including safety-relevant functions and systems. This applies to all test tasks (from function testing to release tests, testing a single ECU or an ECU network, and so on) and also to different vehicle domains: The drivetrain, vehicle dynamics, driver assistance systems, interior/comfort systems and infotainment are all tested by HIL simulation. This paper describes the role of HIL simulation in the development of safety-relevant systems. It explains the requirements defined by ISO 26262 for HIL testing and for HIL systems used in developing safety-relevant systems, and how these requirements can be met.