Time for primary review 34 days. Since the first report of a role for nitric oxide (NO) in modulating myocardial contractile function in 1991 [1], an enormous number of studies have been published in this field (recently reviewed in Refs. [2–4]). It is now recognised that, under physiological conditions, the major sources of NO that are important for contractile regulation are (1) endothelial-type nitric oxide synthase (eNOS) expressed in cardiac endothelial cells, and (2) eNOS expressed in cardiac myocytes themselves. In a variety of pathological situations, contractile function may also be influenced by inducible NOS (iNOS) expressed in several cell types, including infiltrating inflammatory cells, coronary microvascular and endocardial endothelial cells, coronary vascular smooth muscle, and cardiac myocytes. In contrast to the relatively well-defined, essentially species-independent primary action of NO in the vasculature (i.e., mediation of endothelium-dependent vasodilatation), in the heart multiple and sometimes contradictory actions of NO have been reported (Table 1). Some of these actions may be species-specific while others have not always been reproduced by independent laboratories despite the use of apparently similar experimental preparations and protocols. Apart from species and methodological differences, additional relevant factors that are likely to influence the response to NO include: the cellular source of NO, the amount released (or experimentally studied), prevailing redox balance and antioxidant status, the target tissue (e.g., atrial or ventricular tissue), interactions with neurohumoral and other stimuli, the presence of immune activation or disease, and the activation of distinct cGMP-dependent and -independent subcellular signal transduction pathways. View this table: Table 1 Reported actions of NO on the heart. Due to constraints of space, only a limited number of original references have been cited. Many other original references may be found in the bibliography of Refs. [2–4] Most studies that have investigated the effects of NO on contractile function have focused on … * Corresponding author. Tel.: +32-53-724-433