Alterations in intracellular signalling pathways such as the mitogen-activated protein kinases (MAPKs) are key common mechanisms of tumour development and progression. As such, there has been intense research into developing drugs that can inhibit or attenuate intracellular signalling. In recent years, there has been increasing recognition that the cell already has innate negative regulatory proteins that achieve this in normal homeostasis. These regulators provide a feedback inhibitory mechanism that controls the intensity and duration of activated signalling by exogenous stimuli. Members of this group include Raf kinase inhibitor protein 1, the MAPK phosphatases, the SPROUTY and SPRED families and similar expression to FGF. A number of studies have now demonstrated significant alterations in expression of negative regulators in malignant tissue in different cancer types. In functional studies, manipulated expression of these regulators has been shown to significantly influence tumour cell behaviour and phenotype. Here, we summarise the evidence for the functional expression of negative signalling regulators in tumour growth and progression and discuss their potential role as cancer biomarkers and targets for novel drug therapy.