The root apex contains meristematic cells that determine root growth and architecture in the soil. Specific transcription factor (TF) genes in this region may integrate endogenous signals and external cues to achieve this. Early changes in transcriptional responses involving TF genes after a salt stress in Medicago truncatula (Mt) roots were analysed using two complementary transcriptomic approaches. Forty-six salt-regulated TF genes were identified using massive quantitative real-time RT-PCR TF profiling in whole roots. In parallel, Mt16K+ microarray analysis revealed 824 genes (including 84 TF sequences) showing significant changes (p < 0.001) in their expression in root apexes after a salt stress. Analysis of salt-stress regulation in root apexes versus whole roots showed that several TF genes have more than 30-fold expression differences including specific members of AP2/EREBP, HD-ZIP, and MYB TF families. Several salt-induced TF genes also respond to other abiotic stresses as osmotic stress, cold and heat, suggesting that they participate in a general stress response. Our work suggests that spatial differences of TF gene regulation by environmental stresses in various root regions may be crucial for the adaptation of their growth to specific soil environments.