Pericytes are distinctive regulators of vascular morphologenesis and function during vascular development and homeostasis. Pericytes have recently come into focus as implications of aberrant interactions between pericytes and endothelial cells in number of pathological angiogenesis conditions, including diabetic retinopathy and tumor angiogenesis. Pericyte dropout is a hallmark of early diabetic retinopathy. Abnormal angiopoietin (Ang)-Tie-2 signaling is one principal system participating in pericyte/endothelial cell dissociation during early stages of diabetic retinopathy. Angiopoietin 2 (Ang-2) is among the relevant growth factors induced by hypoxia and plays an important role in the initiation of retinal neovascularization and cause pericyte loss. Furthermore, high levels of VEGF synergize Ang-Tie-2 signaling during the development of diabetic retinopathy. An accelerated rate of clinical development Ang-Tie-2-manipulating drugs requests a better mechanistic understanding the connection between pericytes and Ang-Tie-2 systems both under normal and disease conditions. We summarize recent advances in pericyte study in conjunction with Ang-Tie-2 signaling and also discuss possible therapeutic strategies for diabetic retinopathy by targeting pericytes through manipulating Ang-Tie-2 signaling.