It is well established that prolonged hyperglycemia may be a key contributor in the development of vascular complications in diabetes leading to vascular disease. An important feature of vascular disease is abnormal growth, proliferation, migration and hypertrophy of vascular smooth muscle cells (VSMC). However, the precise molecular events linking hyperglycemia with the abnormal VSMC functions remain poorly characterized. Interestingly, recent work has shown that exposure of VSMC with high glucose activates signal transduction networks responsible for mediating the proliferative and growth promoting responses. These include activation of specific isoforms of protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), nuclear transcription factors, Janus-family of activated kinases (JAKs) and signal transducers and activators of transcription (STAT). Since reactive oxygen species (ROS) which are generated in response to hyperglycemia stimulate signaling pathways similar to hyperglycemia and many of the growth promoting effects of hyperglycemia are blocked by antioxidant, a key role of ROS in mediating the cellular responses of hyperglycemia has been suggested. Therefore, this article aims to summarize some of the key studies on hyperglycemia-induced cell signaling pathways in VSMC in relation to their potential role in the development of vascular disease in diabetes.