The Cre/loxP system is a widely applied technology for site-specific genetic manipulation in mice. This system allows for deletion of the genes of interest in specific cells, tissues, and whole organism to generate a diversity of conditional knockout mouse strains. Additionally, the Cre/loxP system is useful for development of cell- and tissue-specific reporter mice for lineage tracing, and cell-specific conditional depletion models in mice. Recently, the Cre/loxP technique was extensively adopted to characterize the monocyte/macrophage biology in mouse models. Compared to other relatively homogenous immune cell types such as neutrophils, mast cells, and basophils, monocytes/macrophages represent a highly heterogeneous population which lack specific markers or transcriptional factors. Though great efforts have been made toward establishing macrophage-specific Cre driver mice in the past decade, all of the current available strains are not perfect with regard to their depletion efficiency and targeting specificity for endogenous macrophages. Here we overview the commonly used Cre driver mouse strains targeting macrophages and discuss their major applications and limitations.