To understand the large inter-species variation in the drug effect on repolarization, and to identify the most human like species, the properties of the rapid (IKr) and the slow (IKs) components of the delayed rectifier potassium currents were compared in myocytes isolated from undiseased human donor (HM), and from three commonly used animal model, the dog (DM), rabbit (RM) and guinea pig (GM) ventricles by applying the patch-clamp and conventional microelectrode techniques at 37 °C. The amplitude of the IKr tail current measured at -40 mV after, a 1 s long test pulse to 20 mV, was very similar in HM and DM (0.35±0.07 and 0.38±0.02 pA/pF, respectively, n=12-15) but larger in RM and GM (0.66±0.05 pA/pF and 1.0±0.08 pA/pF, respectively, n=10). The IKs tail current was considerably larger in GM (amplitude at -40 mV, after a 5 s long test pulse to 50 mV was 3.3±0.6 pA/pF, n=10) than in RM (1.22±0.7 pA/pF, n=7) and DM (0.9±0.05 pA/pF, n=24). In HM IKs tail was even smaller than in DM (0.2±0.05 pA/pF, n=14). IKr activated rapidly and monoexponentially in each studied species. The corresponding activation time constants measured at 30 mV were: 36±3 ms in HM, 53±6 ms in DM, 35±3 ms in RM and 30±2 ms in GM, respectively (n=6-26). The deactivation of IKr in HM, DM and RM measured at -40 mV, after a pulse to 30 mV was slow and biexponential (t1=0.6±0.05 s and t2=6.7±0.9 s in HM; t1=0.4±0.02 s and t2=3.3±0.3 s in DM ; t1=0.6±0.03 s and t2=6.5±0.3 in RM, respectively, n=8-26), while in GM the IKr tail current was best fitted triexponentially (t1=0.14±0.01 s, t2=0.8±0.01 s and t3=6.6±.06 s, n=10). IKs measured at 30 mV, activated slowly and had apparently a monoxponential time course in HM, DM and RM (t=0.9±0.2 s in HM, t=1±0.1 s in DM, and t=0.8±0.05 in RM, respectively, n=6-21). In contrast, in GM the activation was clearly biexponential (t1=0.5±0.02 s and t2=3.2±0.01 s, n=10). In HM, DM and RM IKs deactivation measured at -40 mV, was fast and monoexponential (t=0.15±0.02, t=0.14±0.01 s and t=0.16±0.05, respectively, n=6-22), while in GM, in addition to the fast component (t1=0.16±0.01 s, A1=860±98 pA) an another slower component was also revealed (t2=0.6± 0.1 s, A2=670±79 pA, n=10). Selective IKr blockade resulted in substantial and comparable APD lenghthening in all species, while IKs blockade lengthened significantly APD only in GM, but not in HM, DM and RM (Fig 1). These results suggest that IK in HM resembles that measured in DM and RM, and considerably differs from that observed in GM. These findings suggest that the dog and rabbit IKr and IKs currents resemble more human than guinea pig and these species are more appropriate for preclinical evaluation of new potential drugs expected to affect cardiac repolarization.