Infection of gastric epithelial cells with Helicobacter pylori induces strong proinflammatory responses by activating nuclear transcription factors NF-κB and AP-1. Several reports indicate that multiple bacterial factors and cellular molecules are involved in this signaling. Injected peptidoglycan, CagA or OipA and urease, and at least 16 different signaling cascades have been implicated in H. pylori-induced proinflammatory signaling. Many of these reports are contradictory, thus generating a highly puzzling scenario. Here we discuss the pros and cons of the multiple signaling activities in the induction of proinflammatory responses and associated problems, and give suggestions for finding ways out of this dilemma.