The anaphylatoxin C5a is well-known for its role as chemoattractant and contributes to immune cell recruitment into inflamed tissue and local inflammation. C5a has recently been implicated in modulation of antigen presenting cell function, such as macrophages and dendritic cells, which are pivotal for T cell activation and final T cell effector function. The published data on the effect of C5a on APC function and subsequent adaptive immune responses are in part conflicting, as both pro and anti-inflammatory effects have been described. In this review the opposing effects of C5a on APC function in mice and human are summarized and discussed in relation to origin of the involved APC subset, being either of the monocyte-derived lineage or dendritic cell lineage. In addition, the current knowledge on the expression of C5aR1 and C5aR2 on the different APC subsets is summarized. Based on the combined data, we propose that the differential effects of C5a on APC function may be attributed to absence or presence of co-expression of C5aR2 and C5aR1 on the specific APC.