Heterogeneity in cell signaling pathways is increasingly appreciated as a fundamental feature of cell biology and a driver of clinically relevant disease phenotypes. Understanding the causes of heterogeneity, the cellular mechanisms used to control heterogeneity, and the downstream effects of heterogeneity in single cells are all key obstacles for manipulating cellular populations and treating disease. Recent advances in genetic engineering, including multiplexed fluorescent reporters, have provided unprecedented measurements of signaling heterogeneity, but these vast data sets are often difficult to interpret, necessitating the use of computational techniques to extract meaning from the data. Here, we review recent advances in computational methods for extracting meaning from these novel data streams. In particular, we evaluate how machine learning methods related to dimensionality reduction and classification can identify structure in complex, dynamic datasets, simplifying interpretation. We also discuss how mechanistic models can be merged with heterogeneous data to understand the underlying differences between cells in a population. These methods are still being developed, but the work reviewed here offers useful applications of specific analysis techniques that could enable the translation of single-cell signaling data to actionable biological understanding.