The article is dedicated to the methodology of designing component-in-the-loop (CiL) testing systems for automotive powertrains featuring several drivelines, including variants with individually driven axles or wheels. The methodical part begins with descriptions of operating and control loops of CiL systems having various simulating functionality—from a “lumped” vehicle for driving cycle tests to vehicles with independently rotating drivelines for simulating dynamic maneuvers. The sequel contains an analysis that eliminates a lack of clarity observed in the existing literature regarding the principles of building a “virtual inertia” and synchronization of loading regimes between individual drivelines of the tested powertrain. In addition, a contribution to the CiL methodology is offered by analyzing the options of simulating tire slip taking into account a limited accuracy of measurement equipment and a limited performance of actuating devices. The methodical part concludes with two examples of mathematical models that can be employed in CiL systems to simulate vehicle dynamics. The first one describes linear motion of a “lumped” vehicle, while the second one simulates vehicle’s trajectory motion taking into account tire slip in both the longitudinal and lateral directions. The practical part of the article presents a case study showing an implementation of the CiL design principles in a laboratory testing facility intended for an all-wheel-drive hybrid powertrain of a heavy-duty vehicle. The CiL system description is followed by the test results simulating the hybrid powertrain operation in a driving cycle and in trajectory maneuvering. The results prove the validity of the proposed methodical principles, as well as their suitability for practical implementations.