The healthy intestinal mucosa is home to one of the largest populations of macrophages (mvarphi) in the body [Lee SH, Starkey PM, Gordon S. Quantitative analysis of total macrophage content in adult mouse tissues. Immunochemical studies with monoclonal antibody F4/80. J Exp Med 1985;161:475-89], yet little is known about their function. Resident mvarphi in the large and small intestine are distinct from other mvarphi populations in the body, with regards to both their functional properties and surface phenotype. They respond in an unconventional manner to inflammatory stimuli, with little upregulation of proteins involved in antigen presentation and T cell co-stimulation, and no production of pro-inflammatory cytokines. This suggests that under resting conditions, intestinal mvarphi may be conditioned to be anti-inflammatory in response to local stimuli such as commensal bacteria. In contrast, during inflammation, intestinal mvarphi exhibit increased bactericidal and inflammatory abilities, promote protective immunity and/or mediate pathology. Thus the status of this cell may be the key to understanding how the intestine maintains a balance between being able to generate protective immunity against pathogens, but still prevent pathological inflammation under normal conditions. In this review, we discuss the current knowledge of intestinal mvarphi biology, and highlight the different levels of immunoregulation which influence these cells, with particular focus on innate pathogen recognition receptor (PRR) function and responsiveness to microbial stimuli.