Monocytes can give rise to either antigen presenting dendritic cells (DCs) or scavenging macrophages. This differentiation is initiated when monocytes cross the endothelium. But the regulation of DC and macrophage differentiation in tissues remains elusive. When stimulated with granulocyte–macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4), monocytes yield DCs. However, we show here that the addition of fibroblasts switches differentiation to macrophages. On contact with monocytes, fibroblasts release IL-6, which up-regulates the expression of functional M-CSF receptors on monocytes. This allows the monocytes to consume their autocrine M-CSF. Thus, the interplay between IL-6 and M-CSF switches monocyte differentiation to macrophages rather than DCs, and IL-6 is an essential factor in the molecular control of antigen presenting cell development.