Among the pathogens that have developed a variety of strategies to overcome the host immune system, is the causative agent of Chagas disease, Trypanosoma cruzi. During a long co-evolution process, the parasite has learned how to live in many different environments, including vertebrate and invertebrate hosts. The parasite has also evolved many invasive strategies, including several different ways to enter the host and also the capacity to target different host tissues. An acute systemic response arises in the host after the rapid parasite colonization, interfering with both innate and adaptive immunity. The capacity of T. cruzi to interfere with humoral and cellular immune responses is demonstrated by the expression of different sets of molecules called virulence factors. Among them, the role of antioxidant enzymes, cruzipain, the Tc85/transialidase superfamily, mucins, MASPs, GPI anchors, complement regulatory proteins and others are discussed in this chapter. The expression of parasite-specific virulence factors allows T. cruzi to overcome host immunity successfully and also to invade and disseminate in many different mammalian hosts. However, the picture that has emerged suggests that the basis and mechanisms of parasite virulence could be more complex than expected. Different aspects such as parasite genetic diversity, the effects of polyparasitism and the potential effects that vertebrate and invertebrate hosts have on parasite virulence and the outcome of natural or experimental infection by T. cruzi should be taken into account in futures studies to understand T. cruzi virulence.