Nowadays, industrials are seeking for models and methods that are not only able to provide efficient overall production performance, but also for reactive systems facing a growing set of unpredicted events. One important research activity in that field focuses on holonic/multi-agent control systems that couple predictive/proactive and reactive mechanisms into agents/holons. Meanwhile, not enough attention is paid to the optimization of this coupling. The aim of this paper is to depict the main research challenges that are to be addressed before expecting a large industrial dissemination. Relying on an extensive review of the state of the art, three main challenges are highlighted: the estimation of the future performances of the system in reactive mode, the design of efficient switching strategies between predictive and reactive modes and the design of efficient synchronization mechanisms to switch back to predictive mode. indicator of the production system, discrete-event observer, flexible manufacturing system.