Monocytes and macrophages are central cells of the innate immune system, responding to a diverse repertoire of pathogens. These cells originate from a common myeloid precursor in the bone marrow and while sharing responsibilities during innate immunity, differ greatly in their lifespan. Normally, blood monocytes live for just few days before undergoing apoptosis. Macrophages, in contrast, live up for months. Monocytes' lifespan can switch dramatically, from prolonged survival during inflammation to apoptosis as inflammation resolves. Interestingly, many of the mechanisms mediating survival during inflammation and cancer also operate in monocyte/macrophage differentiation. Differentiation and inflammatory stimuli determine monocyte/macrophage lifespan, by blocking the apoptotic pathway and activating a myriad of survival pathways. How these complicated networks of survival and apoptotic regulators are integrated remains yet to be fully elucidated. The present review summarizes the different monocytes' subpopulations and their function during pathogen recognition. We discuss the role of the caspases and the mechanisms that determine monocytes/macrophages fate highlighting their significance in the regulation of inflammatory diseases.