The modulation of ion channels, including, but not limited to Ca2+ channels and pores, is emerging as a general mechanism by which nitric oxide (NO) exerts biological signaling. Due to the fact that the bioactivity of NO involves several second messenger systems and is profoundly influenced by multiple environmental stimuli, many seemingly divergent observations may be found in the literature. Accordingly, there is an ongoing controversy regarding the impact of NO on Ca2+ channels. An important theme for NO signaling, which may partly settle the ongoing controversies regarding NO signaling, is the spatial confinement of NO synthases (NOSs) with effector molecules, including ion channels. Perhaps the most important environmental stimulus that influences the bioactivity of NO is redox milieu, which in turn is influenced by the formation of reactive oxygen species and oxygen tension. Here, we review the current knowledge regarding the NOS modulation of Ca2+ channels, emphasizing the cardiovascular, musculoskeletal and central nervous systems.