Glutathione (GSH) is a non-protein thiol compound which has been repeatedly reported to play an important role in plant responses during biotic stresses. However, our knowledge of glutathione-related molecular mechanisms underlying plant defense responses still remains limited. We first discovered that the Arabidopsis thaliana phytoalexin deficient 2-1 (pad2-1) mutant was linked to glutathione deficiency since the mutation was identified in the GSH1 gene encoding the first enzyme of glutathione biosynthesis: Glutamate Cysteine Ligase (GCL). Interestingly, this glutathione-deficient mutant pad2-1 also displays a high susceptibility to a wide range of invaders. We recently reported that the glutathione deficiency in pad2-1 is directly related to a low content of GCL protein. In parallel, we highlighted that the altered redox potential in pad2-1 upregulates the oxidative-stress marker genes GR1, GSTF6 and RbohD during infection with the hemibiotrophic oomycete Phytophthora brassicae. Moreover, the impairment of early signaling events such as plasma membrane depolarization, production of nitric oxide and reactive oxygen species also correlates with the reduced hypersensitive response (HR) observed during P. brassicae infection. Concerning the impaired salicylic acid (SA)-dependent pathway in pad2-1, our results indicated that transcripts of IsoChorismate Synthase1 (ICS1, a main enzyme of SA biosynthesis) do not accumulate in response to pathogen. In this review, we integrate previous knowledge and recent discoveries about pad2-1 to better understand the involvement of glutathione in the pad2-1 pleiotropic phenotype observed during biotic stresses.