Numerous pathway methods have been developed to quantify the signaling state of a cell from gene expression data, usually from the abundance of transcripts of pathway members, and are hence unable to take into account post-translational control of signal transduction. Gene expression signatures of pathway perturbations can capture this, but they are closely tied to the experimental conditions that they were derived from. We overcome both limitations by leveraging a large compendium of publicly available perturbation experiments to define consensus signatures for pathway activity. We find that although individual expression signatures are heterogeneous, there is a common core of responsive genes that describe pathway activation in a wide range of conditions. These signaling footprints better recover pathway activity than existing methods and provide more meaningful associations with (i) known driver mutations in primary tumors, (ii) drug response in cell lines, and (iii) survival in cancer patients, making them more suitable to assess the activity status of signaling pathways.