Genetically encoded imaging reporters introduced into cells and transgenic animals enable noninvasive, longitudinal studies of dynamic biological processes in vivo. The most common reporters include firefly luciferase (bioluminescence imaging), green fluorescence protein (fluorescence imaging), herpes simplex virus-1 thymidine kinase (positron emission tomography), and variants with enhanced spectral and kinetic properties. When cloned into promoter/enhancer sequences or engineered into fusion proteins, imaging reporters allow transcriptional regulation, signal transduction, protein-protein interactions, oncogenic transformation, cell trafficking, and targeted drug action to be spatiotemporally resolved in vivo. Spying on cancer with genetically encoded imaging reporters provides insight into cancer-specific molecular machinery within the context of the whole animal.