The potential role of NO in insulin secretion has been widely disputed, and the results obtained are highly controversial. It has been reported that NO stimulates (Laychock et al., 1991[70]; Schmidt et al., 1992[110]; Willmott et al., 1995[133]; Ding and Rana, 1998[26]; Spinas et al., 1998[119]; Matsuura et al., 1999[84]; Spinas, 1999[118]; Smukler et al., 2002[116]; Nystrom et al., 2012[95]; Gheibi et al., 2017[40]), inhibits (Panagiotidis et al., 1992[101], 1994[99], 1995[100]; Gross et al., 1995[45]; Akesson and Lundquist, 1999[2]; Akesson et al., 1996[3], 1999[1]; Antoine et al., 1996[5]; Salehi et al., 1996[107], 1998[108]; Henningsson and Lundquist, 1998[51]; Henningsson et al., 1999[48], 2000[49], 2001[50]; Tsuura et al., 1998[127]) or has negligible effect (Jones et al., 1992[61]; Gheibi et al., 2018[41]) on insulin secretion in studies using islets and β-cell lines with various types and concentrations of NOS inhibitors and NO donors (Table 2(Tab. 2); References in Table 2: Akesson et al., 1999[1]; Ding and Rana, 1998[26]; Gheibi et al., 2017[40], 2018[41]; Henningsson et al., 2002[52]; Jiminez-Feltstrom et al., 2005[60]; Laychock et al., 1991[70]; Mezghenna et al., 2011[90]; Nystrom et al., 2012[95]; Panagiotidis et al., 1995[100]; Salehi et al., 1998[108]; Smukler et al, 2002[116]; Spinas et al., 1998[119]; Tsuura et al., 1998[127]). In the following sections, we will discuss in more detail how NO may stimulate or inhibit insulin secretion.