Cultivated potato is the world’s number one non-grain food commodity. The late blight pathogen Phytophthora infestans has the capacity to attack both potato foliage and tubers. Importantly, foliar resistance against late blight does not guarantee tuber resistance. Most transcriptome studies that have been performed in potato target foliage and very limited studies target tuber-microbe interactions. To understand potato tuber defense mechanisms and to compare tuber and foliage differences in defense, we conducted a time-course RNA-seq study consisting two genotypes (wild type susceptible and transgenic resistant lines), two treatments, three time points, and three reps for tubers and six samples (at one time point) from the foliage. Over 540 million paired-end Illumina Hi-Seq reads were generated. Each of 87% pass filtered reads were mapped uniquely to one location in the reference genome (a doubled monoploid (DM) line), representing transcripts from over 30000 potato genes. About one million potential SNPs between tetraploid potato and DM reference genome were detected; of which only 60% are located within annotated genic regions. We analyzed the transcription levels of potato genes using various software packages. Over 7500 genes were detected to be differentially expressed (DE) among comparisons. We discovered marked differences between the transcriptomes of wild type susceptible and transgenic resistant lines. Various regulatory and metabolic pathways were identified to distinguish organ-specific and transgene-specific responses. Importantly, the transgenic resistant line pre-initialized the transcription of certain receptor kinases and transcription factors in the tubers, suggesting that pre-priming of defense responses may be critical for successful tuber resistance.