This review aims at answering the following question: how can a researcher be sure to succeed in grafting a protein onto a polymer surface? Even if protein immobilization on solid supports has been used industrially for a long time, hence enabling natural enzymes to serve as a powerful tool, emergence of new supports such as polymeric surfaces for the development of so-called intelligent materials requires new approaches. In this review, we introduce the challenges in grafting protein on synthetic polymers, mainly because compared to hard surfaces, polymers may be sensitive to various aqueous media, depending on the pH or reductive molecules, or may exhibit state transitions with temperature. Then, the specificity of grafting on synthetic polymers due to difference of chemical functions availability or difference of physical properties are summarized. We present next the various available routes to covalently bond the protein onto the polymeric substrates considering the functional groups coming from the monomers used during polymerization reaction or post-modification of the surfaces. We also focus our review on a major concern of grafting protein, which is avoiding the potential loss of function of the immobilized protein. Meanwhile, this review considers the different methods of characterization used to determine the grafting efficiency but also the behavior of enzymes once grafted. We finally dedicate the last part of this review to industrial application and future prospective, considering the sustainable processes based on green chemistry.