In the past few years, concerns of protein-gold nanoparticles (AuNP) interaction have been continuously growing in numerous potential biomedical applications. Despite the advances in tunable size, shape and excellent biocompatibility, unpredictable adverse effects related with protein corona (PC) have critically affected physiological to therapeutic responses. The complexity and uncontrollability of AuNP-PC formation limited the clinical applications of AuNP, e.g. AuNP-based drug delivery systems or imaging agent. Thus, even intensive attempts have been made for in vitro characterizations of PC around AuNP, the extrapolation of these data into in vivo PC responses still lags far behind. However, with accumulated knowledge of corona formation and the unique properties of AuNP, we are now encouraged to move forward to seeking positive exploitations. Herein, we summarize recent researches on interaction of protein and AuNP, aiming at provide a comprehensive understanding of such interaction associated with subsequent biomedical impacts. Importantly, the emerging trends in exploiting of potential applications and opportunities based on protein-AuNP interaction were discussed as well. STATEMENT OF SIGNIFICANCE: Gold nanoparticles (AuNPs) have shown great potentials in biomedical areas. However, its practical use is highly limited by protein corona, formed as a result of protein-AuNP interaction. This protein corona surrounding AuNPs is a new identity and the real substance that the organs and cells firstly encounter, and finally makes the behavior of AuNPs in vivo uncontrollable and unpredictable. Therefore, comprehensively understanding such interaction is of great significance for predicting the in vivo fate of AuNPs and for designing advanced AuNPs systems. In this review, we would provide a detailed description of protein-AuNP interaction and launch an interesting discussion on how to use such interaction for smart and controlled AuNPs delivery, which would be a topic of widespread interest.