In recent years, our ability to unravel the finer details of intracellular signaling has improved remarkably. Technological innovations resulting from the introduction of green fluorescent protein (GFP) have played a significant role in these advances. Fluorescent indicators allow us to visualize events within a cell in real-time and space. This review focuses on indicators that use GFP-based fluorescence resonance energy transfer (FRET) technologies and discusses how these methodologies have given insights into biological questions relating to the spatiotemporal patterns of signaling by cAMP, calcium, receptor tyrosine kinases, and other molecules.