Clinical management of diabetes must overcome the challenge of in vivo glucose sensors exhibiting lifetimes of only a few days. Limited sensor life originates from compromised enzyme stability of the sensing enzyme. Sensing enzymes degrade in the presence of low molecular weight materials (LMWM) and hydrogen peroxide in vivo. Sensing enzymes could be made to withstand these degradative effects by (1) stabilizing the microenvironment surrounding the sensing enzyme or (2) improving the structural stability of the sensing enzyme genetically. We review the degradative effect of LMWM and hydrogen peroxide on the sensing enzyme glucose oxidase (GOx). In addition, we examine advances in stabilizing GOx against degradation using hybrid silica gels and genetic engineering of GOx. We conclude molecularly engineered GOx combined with silica-based encapsulation provides an avenue for designing long-term in vivo sensor systems.