Health and disease are directly related to the RTK-RAS-MAPK signalling cascade. After more than three decades of intensive research, understanding its spatiotemporal features is afflicted with major conceptual shortcomings. Here we consider how the compilation of a vast array of accessory proteins may resolve some parts of the puzzles in this field, as they safeguard the strength, efficiency and specificity of signal transduction. Targeting such modulators, rather than the constituent components of the RTK-RAS-MAPK signalling cascade may attenuate rather than inhibit disease-relevant signalling pathways.