Campylobacter is a major cause of acute bacterial diarrhea in humans worldwide. This study was aimed at summarizing the current understanding of host mechanisms involved in the defense against Campylobacter by evaluating data available from three sources: (i) epidemiological observations, (ii) observations of patients, and (iii) experimental observations including observations of animal models and human volunteer studies. Analysis of available data clearly indicates that an effective immune system is crucial for the host defense against Campylobacter infection. Innate, cell-mediated, and humoral immune responses are induced during Campylobacter infection, but the relative importance of these mechanisms in conferring protective immunity against reinfection is unclear. Frequent exposure to Campylobacter does lead to the induction of short-term protection against disease but most probably not against colonization. Recent progress in the development of more suitable animal models for studying Campylobacter infection has opened up possibilities to study the importance of innate and adaptive immunity during infection and in protection against reinfection. In addition, advances in genomics and proteomics technologies will enable more detailed molecular studies. Such studies combined with better integration of host and pathogen research driven by epidemiological findings may truly advance our understanding of Campylobacter infection in humans.