Problems of water resource systems entail many inherent objectives from cost-related to environmental issues, which are usually in conflict and should be addressed simultaneously in decision-making. Multi-objective optimization algorithms aim to simultaneously satisfy two or more objectives and provide a set of optimal solutions for multi-objective optimization problems. Such algorithms can also improve the accuracy of simulation models, such as artificial neural network and adaptive neuro fuzzy interface system. This chapter first presents essential definitions in multi-objective algorithms and their applications in different areas of water resources systems (i.e., model calibration, water distribution network, reservoir operation and management, water quality, water structure design, and groundwater). It then evaluates performance of a recently proposed and two well-known multi-objective algorithms for solving three problems in the optimal operation of a real multipurpose dam.