Mac‐1 (CD11b/CD18) is a β2 integrin classically regarded as a pro‐inflammatory molecule because of its ability to promote phagocyte cytotoxic functions and enhance the function of several effector molecules such as FcγR, uPAR, and CD14. Nevertheless, recent reports have revealed that Mac‐1 also plays significant immunoregulatory roles, and genetic variants in ITGAM, the gene that encodes CD11b, confer risk for the autoimmune disease systemic lupus erythematosus (SLE). This has renewed interest in the physiological roles of this integrin and raised new questions on how its seemingly opposing biological functions may be regulated. Here, we provide an overview of the CD18 integrins and how their activation may be regulated as this may shed light on how the opposing roles of Mac‐1 may be elicited. We then discuss studies that exemplify Mac‐1's pro‐inflammatory versus regulatory roles particularly in the context of IgG immune complex‐mediated inflammation. This includes a detailed examination of molecular mechanisms that could explain the risk‐conferring effect of rs1143679, a single nucleotide non‐synonymous Mac‐1 polymorphism associated with SLE.