Cells can be considered as integrators of simultaneous stimuli, in which cross-talk between transduction pathways can eventually produce responses that are significantly different from simply additive responses. Synergism represents an efficient means of increasing the amplitude of cellular responses induced by low levels of stimulation. Recently, several kinetic and physicochemical models have been developed to describe and predict synergistic responses. In this article, the mechanisms that control the magnitude and timing of cellular synergism are discussed. We suggest that the analysis of theoretical models could enable a general prediction of synergism despite the presence of signal-specific synergistic responses. In addition, application of the proposed concepts should aid understanding of the wide occurrence of synergism induced by interacting transduction pathways in multi-drug clinical treatment.