Crop production is facing challenges that are likely to worsen due to climate change. Increased frequency of drought, disease epidemics and expanding ecological niche of pathogens are consequences of climate change. The design of smarter disease management strategies is crucial to control current and emerging pathogens. Towards addressing these challenges, we study mechanisms of resistance to economically important fungal pathogens in model and crop plants. Our studies using fungal necrotrophic pathogens identified genes that contribute quantitatively resistance. These include Arabidopsis and tomato protein kinases, transcriptional activators and co-activators, and chromatin modifying enzymes. In sorghum, genes that regulate biosynthesis of the phytoalexin 3-deoxyanthocyanidins that also control seed color were key to grain mold resistance. Recently, host resistance to the hemi-biotrophic pathogen Colletotrichum sublineola, the causal agent of sorghum anthracnose disease, was studied. Many loci conferring complete, broad-spectrum or race specific resistance were defined, of which, four encode canonical NLRs (nucleotide-binding leucine-rich repeat immune sensors). The NLR ANTHRACNOSE RESISTANCE GENE1 (ARG1) is nested in an intron of a cis-natural antisense transcript (NAT) gene. ARG1 is regulated through complex mechanisms involving natural antisense transcripts, transposable elements, and histone methylation. ARG4 and ARG5 are located within complex loci displaying interesting haplotype structures and copy number variation. Our studies unraveled multi-layer molecular mechanisms underlying quantitative resistance to necrotrophic fungi and complete resistance to sorghum anthracnose. The implications of these studies towards understanding molecular mechanisms of resistance as well as avenues for developing resilient crops that can thrive in a changing environment and pathogen dynamics will be discussed.