Systems and methods for simulation with dynamic run-time accuracy adjustment. In one embodiment, a first portion of a sequence of software instruction is simulated by a first simulation model, during a simulation. During the same simulation, a second portion of the sequence is simulated by a second simulation model. State information may be transferred from the first simulation model to the second simulation model. A change from simulating the first portion of a sequence of software instructions by the first simulation model to simulating the second portion of the sequence by the second simulation model may be made responsive to a computer-based determination of an advantage obtained by the change.