Panax ginseng C. A. Meyer is an important traditional herb in eastern Asia. It contains ginsenosides, which are primary bioactive compounds with medicinal properties. Although ginseng has been cultivated since at least the Ming dynasty to increase production, cultivated ginseng has lower quantities of ginsenosides and lower disease resistance than ginseng grown under natural conditions. We extracted root RNA from six varieties of fifth-year P. ginseng cultivars representing four different growth conditions, and performed Illumina paired-end sequencing. In total, 163,165,706 raw reads were obtained and used to generate a de novo transcriptome that consisted of 151,763 contigs(76,336 unigenes), of which 100,648 contigs(66.3%) were successfully annotated. Differential expression analysis revealed that most differentially expressed genes(DEGs) were upregulated(246 out of 258, 95.3%) in ginseng grown under natural conditions compared with that grown under artificial conditions. These DEGs were enriched in gene ontology(GO) terms including response to stimuli and localization. In particular, some key ginsenoside biosynthesis-related genes, including HMG-Co A synthase(HMGS), mevalonate kinase(MVK), and squalene epoxidase(SE), were upregulated in wild-grown ginseng. Moreover, a high proportion of disease resistance-related genes were upregulated in wild-grown ginseng. This study is the first transcriptome analysis to compare wild-grown and cultivated ginseng, and identifies genes that may produce higher ginsenoside content and better disease resistance in the wild; these genes may have the potential to improve cultivated ginseng grown in artificial environments. Panax ginseng CA Meyer is an important traditional herb in eastern Asia. It contains ginsenosides, which are primary bioactive compounds with medicinal properties. Although ginseng has been least the Ming dynasty to increase production, cultivated ginseng has lower quantities of ginsenosides and lower Ginseng cultivars representing four different growth conditions, and performing Illumina paired-end sequencing. In total, 163,165,706 raw reads were obtained and used to generate a de novo transcriptome that consisted of 151,763 contigs (76,336 unigenes), of which 100,648 contigs (66.3%) were successfully annotated. Differential expression analysis revealed that most differentially expressed genes (DEGs) were upregulated (246 out of 258, 95.3%) in ginseng grown under natural conditions compared with that grown under artificial conditions. These DEGs w In particular, some key ginsenoside biosynthesis-related genes, including HMG-Co A synthase (HMGS), mevalonate kinase (MVK), and squalene epoxidase (SE), were upregulated in wild-grown ginseng. Moreover, a high proportion of disease resistance-related genes were upregulated in wild-grown ginseng. This study is the first transcriptome analysis to compare wild-grown and cultivated ginseng, and identifies genes that may produce higher ginsenoside content and better disease resistance in the wild; these genes may have the potential to improve cultivated ginseng grown in artificial environments.