The growing availability of single-cell and spatially-resolved transcriptomics has led to the rapidly growing popularity of methods to infer cell-cell communication. Many approaches have emerged, each capturing only a partial view of the complex landscape of cell-cell communication.Here, we present LIANA+, a scalable framework to decode coordinated inter- and intracellular signalling events from single- and multi-condition datasets in both single-cell and spatially-resolved data. Beyond integrating and extending established methodologies and a rich knowledge base, LIANA+ enables novel analyses using diverse molecular mediators, including those measured in multi-omics data. Accessible as an open-source Python package athttps://github.com/saezlab/liana-py, LIANA+ provides a comprehensive set of synergistic components to study cell-cell communication.Abstract Figure