Human blood has historically been considered a sterile environment. Recently, a thriving microbiome dominated by Firmicutes, Actinobacteria, Proteobacteria, and Bacteroidetes phyla was detected in healthy blood. The localization of these microbes is restricted to some blood cell populations, particularly the peripheral blood mononuclear cells and erythrocytes. It was hypothesized that the blood microbiome originates from the skin–oral–gut axis. In addition, many studies have evaluated the potential of blood microbiome dysbiosis as a prognostic marker in cardiovascular diseases, cirrhosis, severe liver fibrosis, severe acute pancreatitis, type 2 diabetes, and chronic kidney diseases. The present review aims to summarize current findings and most recent evidence in the field.