Infection caused by Aspergillus fumigatus remains a major therapeutic challenge in immunocompromised individuals. Innate immunity represents the first line of defense against pathogens. In the last 20 years, several proteins belonging to this arm of the immune system have been characterized as being endowed with antifungal activity. Among these, the prototype long pentraxin PTX3 has been identified as a non-redundant protective factor against infections caused by A. fumigatus. A number of relevant animal models of invasive aspergillosis have indicated that PTX3 exerts its protective activity in several conditions of immunosuppression. In this article, we review the current understanding of PTX3 mechanisms of action that might be of help in further exploration of the pharmacological activity of this protein against A. fumigatus.