Subcellular dysfunction and impaired metabolism derived from the complex interaction of cytokines and mediators with cellular involvement are on the basis of the cardiovascular response to sepsis. The lethal consequences of an infection are intimately related to its ability to spread to other organ sites and the immune system of the host. About one century ago, William Osler (1849-1919), a Canadian physician, remarkably defined the sequelae of the host response in sepsis: "except on few occasions, the patient appears to die from the body's response to infection rather than from it." Cardiac dysfunction has received considerable attention to explain the heart failure in patients progressing from infection to sepsis, but our understanding of the processes remains limited. In fact, most concepts are linked to a mechanical concept of the sarcomeric structure, and physiological data seems to be often disconnected. Cytokines, prostanoids, and nitric oxide release are high direct impact factors, but coronary circulation and cardiomyocyte physiology also play a prominent role in modulating the effects of monocyte adhesion and infiltration. Damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) are involved in the host response. The identification of microRNAs, as well as the cyclic activation of the inflammatory cascade, has further added complexity to the scene. In this review, we delineate the current concepts of cellular dysfunction of the cardiomyocyte in the setting of sepsis and consider potential therapeutic strategies.