Helicobacter pylori (H. pylori) successfully and chronically colonizes the gastric mucosa of approximately 43% of the world's population. Infection with this organism is the strongest known risk factor for the development of gastric cancer, and disease development is dependent on several interactive components. One H. pylori determinant that augments cancer risk is the strain-specific cag type IV secretion system, which not only translocates a pro-inflammatory and oncogenic protein, CagA, into host cells but also DNA, peptidoglycan, and a lipopolysaccharide intermediate, heptose-1,7-bisphosphate. However, cognate interactions between certain microbial and host constituents can also attenuate pro-inflammatory responses, and H. pylori harbors multiple effectors that function differently than the respective counterparts in other mucosal pathogens. In this review, we discuss current data related to mechanisms utilized by H. pylori to evade the immune response, sustain its longevity in the host, and further disease progression, as well as implications for developing targeted, immune-based eradication strategies.