Aeromonas species are emerging human pathogens, which produce an array of virulence factors and cause diseases ranging from gastroenteritis to systemic infections. These bacteria can be found in food and water and grow well and produce toxins at refrigeration temperatures, which greatly increase the risk of food poisoning. A detailed understanding of host responses to Aeromonas virulence factors is paramount to developing better treatment strategies. One of the important virulence factors of Aeromonas is the cytotoxic enterotoxin, Act, which induces potent inflammatory responses in host cells and is lethal when injected intravenously into mice. Microarray analyses of Act-treated host cells by our laboratory revealed that Act induced host cell signaling and apoptosis of macrophages and colonic epithelial cells. We furthered showed that Act production is regulated by glucose inhibited division gene A (gidA) and an iron-regulated ferric uptake regulatory (fur) gene. In addition to Act, our laboratory recently discovered new virulence factors/mechanisms, including the plasminogen-activating enzyme enolase and a type III secretion system, which contribute to Aeromonas-associated diseases. Current knowledge concerning host responses to these and other Aeromonas virulence factors is discussed.