Human strongyloidiasis is a neglected global parasitic disease that affects large populations, especially in poorer regions of the world. Improved diagnostic tools, including serology and molecular tests, are demonstrating that the prevalence of infection is far higher than previously thought. Most complications arise as a consequence of delayed diagnosis, primarily due to physicians not considering this potentially lethal parasitic infection. The likelihood of developing mild chronic strongyloidiasis or hyperinfection syndrome depends on the status of the host defenses. The critical host responses controlling Strongyloides stercoralis in animal models include eosinophils, neutrophils, and antibodies. Corticosteroid treatment and human T-lymphotropic virus (HTLV)-1 infection predispose to hyperinfection in humans, but how these result in hyperinfection is poorly defined. Improved diagnostic tests and molecular epidemiology are highlighting the underappreciated burden of disease, which could be addressed with mass chemotherapy with proven effective drugs like ivermectin.