A system for control of an internal combustion system having subsystems, each with different response times. Subsystems may include a fuel system, an air handling system, and an aftertreatment system, each being operated in response to a set of reference values generated by a respective target determiner. Calibration of each subsystem may be performed independently. The fuel system is controlled at a first time constant. The air handling system is controlled on the order of a second time constant slower than the first time constant. The aftertreatment system is controlled on the order of a third time constant slower than the second time constant. A subsystem manager is optionally in operative communication with each target determiner to coordinate control. Generally, dynamic parameters from slower subsystems are treated as static parameters when determining reference values for controlling a faster subsystem.