Type 1 or insulin-dependent diabetes mellitus is caused by autoimmune attack and selective destruction of the pancreatic ß cells. Despite the development of various insulin replacement therapies, insulin injection still remains the mainstay treatment for type 1 diabetes. However, exogenous insulin administration cannot achieve the same degree of glycemic control as provided by endogenous insulin produced from the pancreatic ß cells. Insulin gene transfer is being developed to improve the quality of glycemic control by restoring endogenous insulin production in type 1 diabetes. Nevertheless, attempts to achieve adequately regulated insulin production are stymied by the lack of appropriate surrogate cells that are able to detect blood glucose variations and release insulin in a glucose-dependent manner. Although limited success has been made to control insulin gene expression in ectopic cells using hormone / glucose regulated expression systems, these transcriptionally regulated systems are relatively slow in the “on-” and “off”-kinetics of insulin production, raising a serious safety concern for clinical application. In this article, we will review recent advances made to address this concern and highlight the importance of insulin gene transfer to cell types that possess an intrinsic ability to kinetically mimic the pancreatic ß cells in terms of glucose-responsive insulin secretion.