A generic methodology to generate optimal controlled dynamic prescriptive route guidance to be disseminated by means of variable message signs (VMSs) is presented. The methodology is generic in the sense that it can be used on any network topology and network model, with any number of VMSs, for different traffic scenarios (e.g., recurrent congestion, accidents, or special events); is based on a flexible, user-defined objective function; and will work as long as feasible route alternatives exist. The presented methodology calculates prescriptive VMS settings with the objective of minimizing the total generalized travel time. An evolutionary algorithm is used to generate and optimize VMS scenarios. A new traffic model, DSMART, has been developed to assess the quality of the route guidance. A prototype of the guidance system has been developed in Matlab and applied in a case study of Rotterdam, Netherlands, by using a network representation of the motorway with six different VMSs and the connected urban network. Results from the case study prove the generic nature of the methodology and its ability to improve overall network conditions for various traffic scenarios.