Medical literature and teaching typically describe platelets in a simplistic manner as the cellular mediators of thrombosis. While this is a very important platelet function, platelets also have diverse roles in regulating all phases of immune responses in both health and disease. We now know that platelets maintain vascular integrity and limit some immune responses in healthy states, but upon vascular or tissue injury or infection, platelets are integral to initiating and accelerating immune responses in addition to limiting bleeding. Megakaryocytes are the platelet precursor cell found primarily in the bone marrow, but also present in the spleens and lungs of mammals. Megakaryocytes are immunologically dynamic with possible ploidy associated immune differentiation and have roles in immune maintenance and differentiation. There is more than one path to megakaryocyte production with the relative input of the “alternate pathway” dependent on age and the inflammatory environment. Its impact on cardiovascular disease development, however, is less known. In this chapter, we describe immune functions for platelet and megakaryocytes, how they may be shaped, and their functional impact on health and disease.