Chronic pain is a highly unmet clinical need. However, the voltage-gated sodium (Nav) channel Nav1.7 has emerged as an attractive target in the treatment of pain [1]. Expressed preferentially in nociceptive dorsal root ganglion neurons, Nav1.7 functions at the cell membrane to transmit peripherally generated pain signals towards the central nervous system [2]. Manipulation of Nav1.7 trafficking mechanisms to decrease the number of these channels expressed at the cell membrane is a promising approach to reducing the sensation of pain. However, very little is currently known about the mechanisms regulating Nav1.7 cell surface expression. Nav channels are composed of four 6-transmembrane domains (I to IV), and have cytosolic N- and C-terminal domains [3]. To examine trafficking by conventional imaging approaches, we have introduced haemagglutinin A (HA) and bungarotoxin binding site (BBS) epitopes into three extracellular loops of the channel. Introduction of these epitopes reduced the surface expression of the channel, preventing the use of this approach to study trafficking. We have thus employed an indirect approach where we have expressed the cytosolic domains of Nav1.7 (from an IRES- EYFP vector) in HEK293 cells stably expressing the channel, and measured channel cell surface expression using the whole-cell patch-clamp method and cell surface biotinylation. The rationale was that the presence of active trafficking motifs within these domains would exert a dominant negative effect on Nav1.7 trafficking, resulting in a change in the cell surface expression of the channel. We found that neither the N-terminus nor inter-domain loop 3 (IDL3) significantly altered Nav1.7 surface expression. It was unclear whether this result was due to inadequate expression of the domains, or because of a lack of effect of the domains. Taken together, applying conventional approaches to investigate Nav1.7 trafficking has proven unsuccessful. In a parallel approach, we have substituted the cytosolic domain of human CD4 with the cytosolic domains of Nav1.7, and examined the effect of the substituted domains on the trafficking of CD4 using immunocytochemistry. Our results show that while human CD4 does not undergo endocytosis when expressed in HEK293 cells, addition of the C-terminus of Nav1.7 results in robust endocytosis, indicating the presence of endocytic signals in the C-terminus of the channel. Consistent with this observed effect, the C-terminus has two consensus endocytosis motifs- a tyrosine-based motif and a dileucine motif. Our results therefore demonstrate that by using reporter proteins such as CD4, it is possible to circumvent the difficulties associated with using full-length Nav1.7, to investigate the trafficking of this channel.