The Hedgehog pathway is a signaling pathway with important roles during embryonic development and adult homeostatic maintenance. In article 2100153, Liu et al. review how various post-translational protein modifications (PTMs) – such as phosphorylation, ubiquitination and SUMOylation – lead to increased accuracy and flexibility in this signaling cascade. In addition, the authors also discuss how the crosstalk between various PTMs and their feedback regulation allows this pathway to efficiently adapt to a broad range of various spatial and temporal inputs.