Ferns from the Azolla genus are highly productive without nitrogen fertilizer because filamentous cyanobacteria, Nostoc azollae, associated with the shoot stem cells, invade leaf cavities for N 2 fixation and reproductive structures for generational transfer. Previously used as nitrogen biofertilizer, their domestication is now considered for circular economy including the sustainable production of plant protein. The symbiosis recently transgressed into molecular research. Sequences from metagenomes of several species are available to study the contribution of the microbiome components to the symbiosis traits. A first assembly and annotation of the reference genome A. filiculoides was released; it allowed reconstruction of tannin biosynthesis, which determines Azolla biomass quality as a feed. Here, we begin with describing novel research areas required to integrate agrosystem development with domestication. We next describe first achievements to control the life cycle of the symbiosis in relation to dissemination, storage, and pre-breeding. We then identify key traits of the symbiosis that will need to be considered to achieve yield stability and discuss these traits with the little mechanistic insight available thus far. We conclude that for rapid breeding, the next vital development will be genome editing of fern host and cyanobacterial symbiont and describe our first steps toward this end.