Mutations or expression levels of cell surface receptors are important contributors in cancer signaling. In many settings, the cellular environment or spatial arrangement of signaling partners is also profoundly altered, resulting in large qualitative changes in signaling outcomes. The changes are far less understood and often not even part of our standard profiling of cancers We primarily study ERBB receptor tyrosine kinases and the Smoothened GPCR and associated changes in the signaling microenvironment that enable oncogenic signaling or give rise to drug resistance. The membrane microenvironment, specifically the glycolipid composition and assembly of qualitatively different signaling hubs, undergoes profound changes as part of a two-way adaptation process. A better understanding of this adaptation process will help in tackling problems of drug resistance, identify novel targets for intervention, and better personalize existing treatments.