This chapter provides an overview of the cellular interactions and the genetic regulations at the bone-implant interface, based on experimental in vivo studies and the available studies in humans. The first part discusses the current knowledge on the cellular and molecular events governing the initial cell recruitment, early inflammation, and the transition from inflammation to bone formation and remodeling during the phases of osseointegration. The modulation of these events, by different implant surfaces, and their relationship with the structural and functional development of the interface, are emphasized. A subsequent section is focused on selected key biological factors, potentially involved in the osteogenic differentiation of mesenchymal stem cells or in coupling of bone formation and remodeling at the interface. Further, possible phenotypic polarizations of macrophages at the interface, in vivo, is discussed. Finally, some insights on possible dysregulations of the molecular activities at the interface, under selected bone-compromising conditions, are provided.