Innate immunity serves as the frontline defence against invading pathogens. Despite decades of research, new insights are constantly challenging our understanding of host-elicited immunity during microbial infections. Recently, two families of humoral innate immune proteins, pentraxins and collectins, have become a major focus of research in the field of innate immunity. Pentraxins and collectins are key players in activating the humoral arm of innate immunity, taking centre stage in immunoregulation and disease modulation. However, increasing evidence suggests that pentraxins and collectins can also mediate pathogenic effects during some infections. Herein, we discuss the protective and pathogenic effects of pentraxins and collectins, as well as their therapeutic significance.