Hookworm disease from Necator americanus and Ancylostoma duodenale affects approximately 700 million people, with N. americanus being the predominant species. Unlike other pathogens (e.g., bacterial infections), where "virulence" is described in regards to acute pathogenesis and case-fatality, hookworms are well-evolved, multicellular parasites that establish long-term infections in their human hosts with a subtle and chronic, but insidious, pathogenesis, usually in the form of iron deficiency anemia from parasite blood feeding that, over time, has devastating effects on the human host especially when it involves children or women of child bearing years. As such, many of the typical terms for "virulence factors" used in other reviews in this special edition cannot be applied to hookworm (e.g., "colonization", "invasion", "or "toxicity"); rather the virulence of hookworm infection comes in terms of their ability to maintain a chronic blood-feeding infection in the lumen of relatively healthy human hosts, an infection that is usually measured in years but can sometimes be measured in decades. In the current manuscript, we describe the routes of invasion hookworms take into their human hosts and the means by which they modulate the human immune system to maintain this long-term parasitism. Little data on hookworm infection comes from actual human infections; instead, much of the data is derived from observations of laboratory animal models, in which hookworms fail to establish this distinctive "chronic infection," either due to physiological or immunological responses of these animal models. Hence, the mode and effects of chronic immunity must be extrapolated from this very different sort of infection to humans. Herein, we aim to synthesize immunological information from both types of models in the context of immune regulation and protection in order to identify future research focuses for the development of new treatment alternatives (i.e. drugs and vaccines).