Biologic response to orthopedic implants debris is central to clinical performance. Eventual implant loosening due to aseptic osteolysis has been attributed to local inflammatory responses to wear and corrosion products that are produced by articulating implant interfaces. The response to implant debris is dominated by local immune activation, e.g. macrophages. Immune reactivity has been shown to depend on the number of particles produced or the dose (i.e., the concentration of phagocytosable particles per tissue volume, which can be characterized by knowing the size distribution and amount of debris). Elongated particles (fbers) are generally more pro-inflammatory than round particles, and there is a growing consensus that metals particles are more proinflammatory than polymers in vivo. Generally, to produce an in vitro inflammatory response, particles need to be less than 10 mum, i.e. phagocytosable. However, both soluble and particulate debris derived from Co-Cr-Mo alloy implants can induce monocyte/macrophage activation and secretion of pro-inflammatory cytokines such as IL-1beta, TNFalpha, IL-6 and IL-8 via up-regulation of transcription factor NFkappabeta, and activation of inflammasome danger signaling in human macrophages. Not only does activation of local (and systemic) inflammation result in decreased osteoblast function but osteoclast activity increases. Some people are more predisposed to implant debris induced inflammation and metal "allergy" testing services are becoming available. New pathways of implant debris-induced inflammatory reactions continue to be discovered, such as the "danger signaling" inflammasome pathway, which provides new targets for pharmaceutical intervention and improved implant performance.