Summary: The innate immune system consists of a cellular arm and a humoral arm. Components of humoral immunity include diverse molecular families, which represent functional ancestors of antibodies. They play a key role as effectors and modulators of innate resistance in animals and humans, interacting with cellular innate immunity. The prototypic long pentraxin, pentraxin 3 (PTX3), represents a case in point of this interplay. Gene targeting of this evolutionarily conserved long pentraxin has unequivocally defined its role at the crossroads of innate immunity, inflammation, matrix deposition, and female fertility. Phagocytes represent a key source of this fluid-phase pattern recognition receptor, which, in turn, facilitates microbial recognition by phagocytes acting as an opsonin. Moreover, PTX3 has modulatory functions on innate immunity and inflammation. Here, we review the studies on PTX3 which emphasize the complexity and complementarity of the crosstalk between the cellular and humoral arms of innate immunity.