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From gene expression profiles, it is desirable to rebuild cellular dynamic regulation networks to discover more delicate and substantial functions in molecular biology, biochemistry, bioengineering, and pharmaceutics. The S-system model is suitable to characterize biochemical network systems and capable of analyzing the regulatory system dynamics. However, the inference of an S-system model of N-gene genetic networks has 2N(N + 1) parameters in a set of nonlinear differential equations to be optimized. This paper proposes an intelligent two-stage evolutionary algorithm (iTEA) to efficiently infer the S-system models of genetic networks from time-series data of gene expression. To cope with the curse of dimensionality, the proposed algorithm consists of two stages, where each uses a divide-and-conquer strategy. The optimization problem is first decomposed into N subproblems having 2(N + 1) parameters each. At the first stage, each subproblem is solved using a novel intelligent genetic algorithm (IGA) with intelligent crossover based on an orthogonal experimental design (OED). At the second stage, the obtained N solutions to the N subproblems are combined and refined using an OED-based simulated annealing algorithm for handling noisy gene expression profiles. The effectiveness of iTEA is evaluated using simulated expression patterns with and without noise running on a single-processor PC. It is shown that 1) IGA is efficient enough to solve subproblems, 2) IGA is significantly superior to the existing method GA with simplex crossover (SPXGA), and 3) iTEA performs well in inferring S-system models for dynamic pathway identification.