Although the theoretical possibility of oscillations in MAPK signalling has long been described, experimental validation has proven more elusive. In this study we observed oscillations in MAPK and PI3K signalling in breast cancer cells in response to epidermal growth factor receptor-family stimulation. Using systems level analysis with a kinetic model, we demonstrate that receptor amplification, loss of transcriptional feedback, or pathway crosstalk, are responsible for oscillations in MAPK and PI3K signalling. Transcriptional profiling reveals architectural motifs likely to be responsible for feedback control of oscillations. Overexpression of the HER2 oncogene and inhibition of transcriptional feedback increase the amplitude of oscillations and provide experimental validation of the computational findings.