An unanswered question in the field of signal transduction research is how different signaling pathways are activated with strict specificity in a temporally and spatially controlled manner. Because extracellular ligands and membrane receptors constitute the first signaling modalities for most pathways, selectivity in ligand-receptor binding likely dictates the outcome of downstream signaling events. Unfortunately, possible complexities underlying ligand-receptor interactions are often overlooked. Here, we discuss basic principles of signal transduction initiated at the cell membrane, with the Wnt pathway, which harbors a multitude of ligands and receptors, as an example.