Macrophages are mononuclear innate immune cells which have become of increasing interest in the fields of disease and regeneration, as their non-classical functions have been elucidated in addition to their classical inflammatory functions. Macrophages can regulate tissue remodeling, by both mounting and reducing inflammatory responses; and exhibit direct communication with other cells to drive tissue turnover and cell replacement. Furthermore, macrophages have recently become an attractive therapeutic target to drive tissue regeneration. The major salivary glands are glandular tissues that are exposed to pathogens through their close connection with the oral cavity. Moreover, there are a number of diseases that preferentially destroy the salivary glands, causing irreversible injury, highlighting the need for a regenerative strategy. However, characterization of macrophages in the mouse and human salivary glands is sparse and has been mostly determined from studies in infection or autoimmune pathologies. In this review, we describe the current literature around salivary gland macrophages, and speculate about the niches they inhabit and how their role in development, regeneration and cancer may inform future therapeutic advances.