Abstract Communication with the environment is an essential characteristic of the living cell, even more when considering the origins and evolution of multicellularity. A number of changes and tinkering inventions were necessary in the evolutionary transition between prokaryotic and eukaryotic cells, which finally made possible the appearance of genuine multicellular organisms. In the study of this process, however, the transformations experimented by signaling systems themselves have been rarely object of analysis, obscured by other more conspicuous biological traits: incorporation of mitochondria, segregated nucleus, introns/exons, flagellum, membrane systems, etc. Herein a discussion of the main avenues of change from prokaryotic to eukaryotic signaling systems and a review of the signaling resources and strategies underlying multicellularity will be attempted. In the expansion of prokaryotic signaling systems, four main systemic resources were incorporated: molecular tools for detection of solutes, molecular tools for detection of solvent (Donnan effect), the apparatuses of cell-cycle control, and the combined system endocytosis/cytoskeleton. The multiple kinds of enlarged, mixed pathways that emerged made possible the eukaryotic revolution in morphological and physiological complexity. The massive incorporation of processing resources of electro-molecular nature, derived from the osmotic tools counteracting the Donnan effect, made also possible the organization of a computational tissue with huge information processing capabilities: the nervous system. In the central nervous systems of vertebrates, and particularly in humans, neurons have achieved both the highest level of molecular-signaling complexity and the highest degree of information-processing adaptability. Theoretically, it can be argued that there has been an accelerated pace of evolutionary change in eukaryotic signaling systems, beyond the other general novelties introduced by eukaryotic cells in their handling of DNA processes. Under signaling system's guidance, the whole processes of transcription, alternative splicing, mobile elements, and other elements of domain recombination have become closely intertwined and have propelled the differentiation capabilities of multicellular tissues and morphologies. An amazing variety of signaling and self-construction strategies have emerged out from the basic eukaryotic design of multicellular complexity, in millions and millions of new species evolved. This design can also be seen abstractly as a new kind of quasi-universal problem-solving ‘engine’ implemented at the biomolecular scale—providing the fundamentals of eukaryotic ‘intelligence’. Analyzing in depth the problem-solving intelligence of eukaryotic cells would help to establish an integrative panorama of their information processing organization, and of their capability to handle the morphological and physiological complexity associated. Whether an informational updating of the venerable “cell theory” is feasible or not, becomes, at the time being – right in the middle of the massive data deluge/revolution from omic disciplines – a matter to careful consider.