The smooth identification and low-cost production of highly specific agents that interfere with signaling cascades by targeting an active domain in surface receptors, cytoplasmic and nuclear effector proteins, remain important challenges in biomedical research. We propose that peptide aptamers can provide a very useful and new alternative for interfering with protein-protein interactions in intracellular signal transduction cascades, including those emanating from activated receptors for growth factors. By their targeting of short, linear motif type of interactions, peptide aptamers have joined nucleic acid aptamers for use in signaling studies because of their ease of production, their stability, their high specificity and affinity for individual target proteins, and their use in high-throughput screening protocols. Furthermore, they are entering clinical trials for treatment of several complex, pathological conditions. Here, we present a brief survey of the use of aptamers in signaling pathways, in particular of polypeptide growth factors, starting with the published as well as potential applications of aptamers targeting Epidermal Growth Factor Receptor signaling. We then discuss the opportunities for using aptamers in other complex pathways, including Wnt/beta-catenin, and focus on Transforming Growth Factor-beta/Smad family signaling.