Individual bacteria that are genetically identical appear to exhibit substantial variation in cellular behavior. Samadani et al. turn their attention to directional sensing by the eukaryotic slime mold Dictyostelium discoideum, exposing the cells to a reproducible concentration gradient of adenosine 3′,5′-monophosphate (cAMP) and monitoring the localization, polarization, and polarization angle of a reporter of phosphatidylinositol 3,4,5-trisphosphate. Individual cells responded to repeated exposure to the gradient very reproducibly; however, the population response was much more variable. Some cells produced a robust response to the cAMP gradient, but others produced a smaller response to the gradient. Samadani et al. introduce a model to explain this phenomenon that includes a contribution of cellular internal asymmetry representing a static intracellular signal, which could arise through spatial inhomogeneities in signaling molecules, and the external signal (the gradient of cAMP). In this model, cells exposed to a uniform concentration of cAMP polarize in the direction of their intracellular signal. Cells in which the cAMP gradient is in the same direction as the intracellular signal produce the largest effective response in the direction of the gradient. Cells in which the cAMP gradient is misaligned with the intracellular signal produce a less robust response to the gradient. Thus, the model suggests that the response of an individual cell appears to depend on an intracellular signal that is random within the population and that the population response is dominated by the cells in which the extracellular signal and the intracellular signal align.