In recent years, there has been a need to seek adequate preventive measures to deal with contamination in water distribution networks that may be related to the accidental contamination and the deliberate injection of toxic agents. Therefore, it is very important to create a sensor system that detects contamination events in real time, maintains the reliability and efficiency of measurements, and limits the cost of the instrumentation. To this aim, two problems have to be faced: practical difficulties connected to the experimental verification of the optimal sensor configuration efficiency on real operating systems and challenges related to the reliability of the network modelling approaches, which usually neglect the dispersion and diffusion phenomena. The present study applies a numerical optimization approach using the NSGA-II genetic algorithm that was coupled with a new diffusive-dispersive hydraulic simulator. The results are compared with those of an experimental campaign on a laboratory network (Enna, Italy) equipped with a real-time water quality monitoring system and those of a full-scale real distribution network (Zandvoort, Netherlands). The results showed the importance of diffusive processes when flow velocity in the network is low. Neglecting diffusion can negatively influence the water quality sensor positioning, leading to inefficient monitoring networks.