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This extensively revised second edition of Modeling Biological Systems: Principles and Applications describes the essentials of creating and analyzing mathematical and computer simulation models for advanced undergraduates and graduate students. It offers a comprehensive understanding of the underlying principle, as well as details and equations applicable to a wide variety of biological systems and disciplines. Students will acquire from this text the tools necessary to produce their own models. The text contains two major sections: Principles and Applications. The first section discusses the principles of biological systems with a thorough description of the essential modeling activities of formulation, implementation, validation, and analysis. These activities are illustrated by a set of example models taken from recent and classical literature, chosen for their breadth of coverage and current timeliness. The new edition updates extensively many of these topics, especially quantitative model formulation, validation and model discrimination using information theory measures and Bayesian probability, and stability analysis and non-dimensionalization.