To evalúate the mechanisms involved in macrophage proliferation and activation, we studied the regulation of the nucleoside transport systems. In murine bone marrow‐derived macrophages, the nucleo‐sides required for DNA and RNA synthesis are recruited from the extracellular medium. M‐CSF induced macrophage proliferation and DNA and RNA synthesis, whereas interferon γ (IFN‐γ) led to activation, blocked proliferation, and induced only RNA synthesis. Macrophages express at least the concentrative systems N1 and N2 (CNT2 and CNT1 genes, respectively) and the equilibrative systems es and ei (ENT1 and ENT2 genes, respectively). Incubation with M‐CSF only up‐regulated the equilibrative system es. Inhibition of this transport system blocked M‐CSF‐dependent proliferation. Treatment with IFN‐γ only induced the concentrative N1 and N2 systems. IFN‐γ also down‐regulated the increased expression of the es equilibrative system induced by M‐CSF. Thus, macrophage proliferation and activation require selective regulation of nucleoside transporters and may respond to specific requirements for DNA and RNA synthesis. This report also shows that the nucleo‐side transporters are critical for macrophage proliferation and activation.