Salinity tolerance in rice, like in other glycophytes, is a function of cellular ion homeostasis. The large divergence in ion homeostasis between the salt-tolerant FL478 and salt-sensitive IR29 rice varieties can be exploited to understand mechanisms of salinity tolerance. Physiological studies indicate that FL478 shows a lower Na+ influx, a reduced Na+ translocation to the shoot, and maintains a lower Na+:K+ ratio. To understand the basis of these differences, a comparative investigation of transcript regulation in roots of the two cultivars was undertaken. This analysis revealed that genes encoding aquaporins, a silicon transporter, and N transporters are induced in both cultivars. However, transcripts for cation transport proteins including OsCHX11, OsCNGC1, OsCAX, and OsTPC1 showed differential regulation between the cultivars. The encoded proteins are likely to participate in reducing Na+ influx, lowering the tissue Na+:K+ ratio and limiting the apoplastic bypass flow in roots of FL478 and are therefore important new targets to improve salt tolerance in rice.