The activated sludge process (ASP) is the most commonly used process for wastewater treatment. Improving its performance is necessary from economic and environmental point of views. In this context, dynamic optimization is a powerful tool for assisting engineers in determining optimal operations and designs for ASPs. However, the real optimality of the solution strongly depends on the optimization problem statement, for which unfortunately, there is no standard or commonly accepted formulation. In a hopeful attempt to provide a guideline for future works on the topic, this paper reviews the literature devoted to optimal control and design of ASPs. The main issues to be addressed in order to get reliable solutions are discussed , among which: (1) Managing the inevitable mismatch between the model predictions and the real ASP operation. (2) Dealing with the unpredictable variations in the wastewater characteristics. (3) Accounting for the slowest dynamic processes occurring in ASPs. (4) Appropriately selecting the decision variables and the flowsheet structure in order to simplify the problem formulation from a mathematical perspective. (5) Conveniently choosing the cost functions expressions/correlations. (6) Successfully selecting the mathematical constraints in order to guarantee physically relevant operations.