The defense system of plants is comprised of various R-protein, which usually contain nucleotide binding site-Leucine rich repeat (NBS-LRR) domain. In addition, non NBS-LRR genes like SAMDC, ODC, SPM, SPD, HSP90, HSP17, HSF-A and HSF-B also prepare plants to combat biotic stress. MicroRNAs (miRNAs) represent the 2nd layer of defense and play a pivotal role behind the scene. This study was conducted to explore the role of these three components, in provoking immune response of cucumber plants after challenging with cucumber mosaic virus (CMV). Screening of 21 genotypes of cucumber against CMV showed Ames-26917 as the most susceptible and identified P1-618950 as the most resistant one. Phylogenetic analysis and sequence alignment of 57 NBS genes, showed various classes of the NBS- gene family. Transcript profiling of 17 CC domain-containing genes along with non-NBS-LRR genes in the virus inoculated plants of selected resistant and susceptible genotypes at 8 DPI and 15 DPI was carried out by real time RT-PCR. In the resistant genotype, relatively higher transcript levels of NBS-1, NBS-5 and NBS-7 were observed at 15 DPI in infected plants as compared to non-infected control. At 8 DPI, the transcript accumulation of the NBS genes was down-regulated upon infection. In the susceptible genotype, the same trend was observed but the transcripts were relatively lower in concentration as compared to resistant genotypes. In non-infected plants, no change of transcript level was observed between 8 DPI and 15 DPI. Transcript analysis of non-NBS genes showed similar trend of transcript accumulation in both, resistant and susceptible genotypes between 8DPI and 15 DPI except for HSP-17, whose transcription was up regulated upon infection at 15 DPI. To explore the potential role of miRNAs in attenuating these genes, bioinformatics prediction of miRNAs, targeting NBS-LRR genes, was conducted. Ten miRNAs showed their complementation with 7 NBS-LRR genes. To validate the role of these miRNAs in attenuating the target genes, co-expression analysis was carried out, which detected these miRNAs only in non-infected cucumber genotypes (and infected as stated below?). This study concluded that cucumber plant’s immune system was not triggered until the virus obtained its threshold level at 15DPI. The non NBS-LRR genes do not seem to play role in preparing the system against biotic stress, except HSP-17, which was upregulated at 15 DPI. The detection of selected miRNAs (396c, 156a, 157b, 159a, 162a, 169a, 169c, 169e, 172d, 390b) only in the infected samples suggested their role in attenuating the expression of NBS-LRR genes but non NBS-LRRs are neutral to the abundance or absence of miRNA before or after infection.