The sigma-1 receptor (Sig-1R), via interaction with various proteins, including voltage-gated and ligand-gated ion channels (VGICs and LGICs), is involved in a plethora of neuronal functions. This capability to regulate a variety of ion channel targets endows the Sig-1R with a powerful capability to fine tune neuronal excitability, and thereby the transmission of information within brain circuits. This versatility may also explain why the Sig-1R is associated to numerous diseases at both peripheral and central levels. To date, how the Sig-1R chooses its targets and how the combinations of target modulations alter overall neuronal excitability is one of the challenges in the field of Sig-1R-dependent regulation of neuronal activity. Here, we will describe and discuss the latest findings on Sig-1R-dependent modulation of VGICs and LGICs, and provide hypotheses that may explain the diverse excitability outcomes that have been reported so far.