INTRODUCTION: Diabetes mellitus (DM) is a challenging chronic disease worldwide. The incidence is expected to rise dramatically by 2030 due to smoking, obesity, and aging population, increasing the public health burden in coming years. Diabetic retinopathy (DR) is a common microvascular complication and a leading cause of blindness among working-age individuals. Understanding the proteomic mechanisms driving disease progression and visual loss is of paramount importance when laying novel strategies for managing patients in clinical practice.AREAS COVERED: We summarize proteomic studies addressing molecular biomarkers in human blood for DR. We discuss methodological advantages and challenges. Proteomic technology advancement has reached a level where even low-abundance proteins related to disease can be detected in blood. The pooled results of these studies suggest that the biomarkers are specific to the disease stage and hold promise for personalized risk stratification in DR.EXPERT OPINION: With the development of advanced mass spectrometry technology for the investigation of biomarkers in blood, this research area is expected to advance in the future. Similarly, it is expected that novel blood-based biomarkers for DR will be validated in international studies and implemented in clinical practice. Therefore, future perspectives hold promises of personalized risk profiling for diagnosis, disease progression, and optimal choice of treatment.