In this paper, the development and testing through simulation of an integrated scheme for aircraft sub-system failure detection and identification (FDI) based on the artificial immune system (AIS) paradigm is presented. The simulation environment includes the NASA Generic Transport Model interfaced with FlightGear. A hierarchical multi-self strategy was used to develop an FDI scheme capable of handling malfunctions of actuators and aerodynamic surface damage. The performance of the FDI scheme has been evaluated in terms of false alarms and successful detection and identification over a wide flight envelope and for a large variety of abnormal conditions. For all cases investigated the performance was very good, confirming the potential of the AIS paradigm to offer a comprehensive solution to the aircraft sub-system FDI problem.