Symbiosis between cyanobacteria and plants is considered pivotal for biological nitrogen deposition in terrestrial ecosystems. Despite the large knowledge in the ecology of plant-cyanobacteria symbioses, little is known about the molecular mechanisms involved in the crosstalk between partners. A SWATH-mass spectrometry has been used to analyse, at the same time, the differential proteome of Oryza sativa and Nostoc punctiforme during the first events of the symbiosis. N. punctiforme activates the expression of thousands of proteins involved in signal transduction and cell wall remodelling, as well as 11 Nod-like proteins that might be involved in the synthesis of cyanobacterial-specific Nod factors. In O. sativa the differential protein expression was connected to a plethora of biological functions including signal transduction, defense-related proteins, biosynthesis of flavonoids and cell wall modification. N. punctiforme symbiotic inspection of O. sativa mutants in the SYM pathway reveals the involvement of this ancestral symbiotic pathway in the symbiosis between the cyanobacterium and the plant.