Sorghum [Sorghum bicolor (L) Moench] is a major cereal crop of global importance. The crop is grown for food, feed, biofuel and other applications. Among major production constraints of the crop worldwide is sorghum anthracnose that is caused by the fungal pathogen Colletotrichum sublineolum. Despite the extensive diversity for genetic resistance to the pathogen in the sorghum natural variation, specific resistance genes have not been identified. Consequently, the molecular mechanisms of resistance to the disease are poorly understood. The paucity of knowledge on resistance genes has hampered crop improvement and studies on mechanisms of resistance to the resistance. In this study, we report the identification of two ANTHRACNOSE RESISTANCE GENES (ARG2 and ARG3) that control sorghum resistance to anthracnose. Initially, by screening a collection of sorghum natural variants, we identified genotypes that carry race specific resistance to strains of the pathogen. Bulked Segregant Analyses of genomic DNA raw-reads (BSA-Seq) in biparental mapping populations followed by recombination and comparative genomic analyses were conducted to determine the specific sequence variation in ARG2 and ARG3 loci that underpin the differences in disease phenotype. The identity of the ARG genes and their genetic link to resistance were validated using independent alleles from distinct germplasm sources. The ARG2 locus harbors a cluster of duplicate NB-LRR genes with complex structural and functional relationships in different sorghum lines. ARG2 encodes a canonical resistance protein with CC-NBS-LRR structure and confers complete resistance to some strains of the pathogen. Near-isogenic lines (NILs) that differ in the ARG2 locus showed that the expression of defense response genes is associated to the resistance and provided further insight to the effect of ARG2 locus on the growth of the resistant lines. The ARG3 locus has significant genomic rearrangements in different sorghum lines and a unique genomic feature in the resistant line. ARG3 is likely a novel resistance gene with no homolog identified in the plant kingdom. Intriguingly, ARG3 is located within a large genomic region showing striking synteny of genes between rice and sorghum. ARG3 confers resistance to a strain of the pathogen that is virulent on sorghum lines that are known for broad-spectrum resistance. The identification of ARG2 and ARG3 will contribute to breeding for sorghum anthracnose resistance and to studies on the genetic control of anthracnose disease. Additional implications of these findings, future studies and the advances made over previous studies are discussed.