There is growing realization that on-line model maintenance is the key to realizing long term benefits of a predictive control scheme. In this work, a novel intelligent nonlinear state estimation strategy is proposed, which keeps diagnosing the root cause(s) of the plant model mismatch by isolating the subset of active faults (abrupt changes in parameters/disturbances, biases in sensors/actuators, actuator/sensor failures) and auto-corrects the model on-line so as to accommodate the isolated faults/failures. To carry out the task of fault diagnosis in multivariate nonlinear time varying systems, we propose a nonlinear version of the generalized likelihood ratio (GLR) based fault diagnosis and identification (FDI) scheme (NL-GLR). An active fault tolerant NMPC (FTNMPC) scheme is developed that makes use of the fault/failure location and magnitude estimates generated by NL-GLR to correct the state estimator and prediction model used in NMPC formulation. This facilitates application of the fault tolerant scheme to nonlinear and time varying processes including batch and semi-batch processes. The advantages of the proposed intelligent state estimation and FTNMPC schemes are demonstrated by conducting simulation studies on a benchmark CSTR system, which exhibits input multiplicity and change in the sign of steady state gain, and a fed batch bioreactor, which exhibits strongly nonlinear dynamics. By simulating a regulatory control problem associated with an unstable nonlinear system given by Chen and Allgower [H. Chen, F. Allgower, A quasi infinite horizon nonlinear model predictive control scheme with guaranteed stability, Automatica 34(10) (1998) 1205-1217], we also demonstrate that the proposed intelligent state estimation strategy can be used to maintain asymptotic closed loop stability in the face of abrupt changes in model parameters. Analysis of the simulation results reveals that the proposed approach provides a comprehensive method for treating both faults (biases/drifts in sensors/actuators/model parameters) and failures (sensor/ actuator failures) under the unified framework of fault tolerant nonlinear predictive control. © 2008 Elsevier Ltd. All rights reserved.