Cellular signaling is essential in information processing and decision-making. Therefore, a variety of experimental approaches have been developed to study signaling on bulk and single-cell level. Single-cell measurements of signaling molecules demonstrated a substantial cell-to-cell variability, raising questions about its causes and mechanisms and about how cell populations cope with or exploit cellular heterogeneity. To gain insights from single-cell signaling data, analysis and modeling approaches have been introduced. This review discusses these modeling approaches, with a focus on recent advances in the development and calibration of mechanistic models. Additionally, it outlines current and future challenges.