Hyperglycaemia is a common physiological response in critically ill patients, and reflects the perturbed metabolic state associated with severe illness. Regulating blood glucose (BG) levels to pre-ICU concentrations may provide patients with a greater chance of survival and reduced complications. However, despite the potential benefits there is still no universally adopted method for regulating BG levels in the ICU, and several large trials have failed to provide a consistent level of BG regulation across multiple centers. Models of the glucose regulatory system together with specialized controllers can assist clinical staff in therapy decisions by optimizing insulin and nutrition dosing. These systems can be readily implemented using existing or commodity equipment. This article presents experiences in implementing such model-based BG control in eight studies across four clinical units in three countries and highlights challenges faced when translating control systems from design and simulation environments to daily bedside clinical usage. Several practical issues need to be addressed for successful clinical implementation. Patient response to glucose and insulin inputs needs to be characterized, and it has been observed that level of insulin response varies significantly between patients and within patients over time. Clinically desired target ranges for BG control often vary by clinic and by year, and thus control schemes are required to adapt. Finally, the design of the system interface plays an important role in merging with local clinical practices and achieving nursing support for the system. Considerable variation exists, not only in the types of patients and observed responses to treatment, but also in the provision of clinical treatment. Thus a balance is required between flexibility and complexity to reduce training time and costs, improve transparency and promote independent clinical uptake.