Integrated Pest Management and Integrated Vector Management worldwide are developed in agriculture and public health to counteract and limit the exponential increasing development of insect resistance to insecticides. However, facing the predominance of some resistant populations, new strategies are urgently needed to target resistant insects. An innovative approach lies in the optimization of commonly used insecticides when combined with chemical or biological synergistic agents. By an increase of intracellular calcium concentration followed by activation of calcium-dependant signalling pathways, the synergistic agents are able to indirectly increase target sites sensitivity to insecticide by inducing conformational change. The synergistic agents are of great interest in optimizing the efficacy of insecticides and in overcoming resistance mechanisms.