Loss of functional β-cell mass is a hallmark of Type 1 and Type 2 Diabetes. Macrophages play an integral role in the maintenance or destruction of pancreatic β-cells. The effect of the macrophage β-cell interaction is dependent on the activation state of the macrophage. Macrophages can be activated across a spectrum, from pro-inflammatory to anti-inflammatory and tissue remodeling. The factors secreted by these differentially activated macrophages and their effect on β-cells define the effect on functional β-cell mass. In this review, the spectrum of macrophage activation is discussed, as are the positive and negative effects on β-cell survival, expansion, and function as well as the defined factors released from macrophages that impinge on functional β-cell mass.