The eosinophil cationic protein (ECP) is a secretory ribonuclease, which is found in the eosinophilic leukocyte and involved in the innate immune system. Its cytotoxic activity is effective against a wide range of pathogens, suggesting a relatively non-specific mechanism of action. We review here the specific antipathogen activities that have been characterized for ECP. Although eosinophils and ECP are primarily associated with the host defense against nonphagocytosable pathogens, such as helminthic parasites, ECP has also an antibacterial activity, which is not shared by the other, closely-related eosinophil ribonuclease, the eosinophil derived neurotoxin (EDN). Although there is no evidence for direct involvement in vivo of eosinophils in the host response to bacterial infection, ECP is active against both Gram-negative and Gram-positive bacterial strains and its mechanism depends on its action both at the bacterial cell wall and cytoplasmic membrane levels. Other antipathogen activities, including antihelminthic activity, are also discussed. Modulation of the protein activity by posttranslational modifications and the currently identified polymorphisms are reviewed. Antimicrobial RNases, as innate immune proteins with anti-infective and immunomodulatory properties, present substantial therapeutic potential in the drug development industry, both in the search of alternative antibiotics and for the treatment of inflammatory disorders.