For growth, survival, communication and homeostasis, cells transport a large number of proteins to the plasma membrane and the extracellular medium by using the secretory pathway. Consequently, to adapt to the surrounding environment and the different intracellular contexts, the secretory pathway needs to accommodate and respond to a plethora of endogenous and exogenous stimuli. It is now well established that several kinases, known to be activated by environmental stimuli, signal from the plasma membrane to the secretory pathway in order to remodel its architecture and modulate the cellular secretion capacity. By contrast, membranes of the early secretory pathway, similar to the endosomal system, can also initiate and modulate signalling cascades, thereby spatially organising cellular signalling and eliciting a different cellular outcome than when signalling is localised to the plasma membrane. This Commentary highlights recent contributions to our understanding of the mutual regulation of the secretory pathway and cellular signalling.