Sepsis is defined as a life-threatening organ dysfunction resulting from a maladaptive host response to an infection. It is considered the most urgent unmet medical need of this time, as it accounts for approximately 20% of all global deaths (Singer et al, 2016; Reinhart et al, 2017; Rudd et al, 2020). Several clinical studies have shown that sepsis leads to intravascular hemolysis, being accompanied with an increased risk of death (Adamzik et al, 2012; Janz et al, 2013; Hartmann & De Groot, 2013; Simon et al, 2014). Despite speculations in literature, the mechanism of hemolysis in sepsis or its contribution to sepsis progression has not been elucidated so far. Next to this, it is speculated that sepsis-induced intravascular hemolysis might lead to the depletion of haptoglobin and hemopexin, thereby resulting in the accumulation of toxic hemolytic byproducts in the blood, including heme. By studying the mechanism of sepsis-induced hemolysis and its consequences (e.g. heme release), we will be able to identify new targets of interest for therapeutic intervention.