Tissue macrophages (Mø) and dendritic cells (DC) are thought to derive from hematopoietic stem cells, which exist in the bone marrow and generate intermediate precursor populations with increasingly restricted lineage potentials. There exists several precursors committed to the Mø and DC lineages; these cells exhibit distinct tropism and function and respond differentially in pathophysiologic conditions. In this review, we consider experimental contexts in which Mø and DC responses in tissue are not only dictated by the local environment, but also by the quantity and quality of newly recruited lineage precursor cells. Consequently, we discuss whether therapeutic control of Mø and DC responses in tissue may be achieved through manipulation of their lineage precursors.