Streptococcus pneumoniae is the most prevalent cause of community-acquired pneumonia and is known to induce apoptosis and necrosis in macrophages in vivo. We analyzed the kinetics of alveolar and lung parenchymal macrophage replacement by newly recruited exudate macrophages in vehicle-treated and S. pneumoniae-challenged bone marrow chimeric CD45.1 mice. After lethal irradiation, CD45.1 alloantigen-expressing recipient mice were transplanted with bone marrow cells from CD45.2 alloantigen-expressing donor mice. After only 24 hours of low-dose S. pneumoniae infection, approximately 60% of CD45.1 pos recipient-type alveolar macrophages (AM) were replaced by CD45.2pos donor-type exudate AM in bronchoalveolar lavage fluid, and this increased to more than 80% on Day 7 of infection. In contrast, lung parenchymal macrophages of S. pneumoniae-infected chimeric CD45.1 mice were replaced by only about 10% by 24 hours, although this increased to over 80% by Days 3 to 7 of infection. This dramatic macrophage turnover was accompanied by early induction of apoptosis/necrosis in donor-type exudate AM peaking at 6 hours after infection, whereas peak apoptosis/necrosis induction in recipient-type AM was delayed until Day 7. Collectively, these data for the first time demonstrate that S. pneumoniae infection of the lung triggers a brisk turnover of both resident and recruited mononuclear phagocyte subsets, and suggest an important role of exudate but not resident macrophages in re-establishing alveolar and lung homeostasis.