The fungus Colletotrichum orbiculare causes watermelon anthracnose and is an important pathogen of watermelon in the United States, causing a significant impact on yield and quality of the produce. The application of fungicides as preventative and post-occurrence control measures is currently being deployed by growers. Further study of the genetic and molecular basis of anthracnose resistance will help in guiding future watermelon breeding strategies. Several conserved virulence factors (effectors) in C. orbiculare have been reported to interact with the host, at times impairing the host immune machinery. A single dominant gene conferring race 1 anthracnose resistance was reported independently on two watermelon germplasm. The recent advances in genomics, transcriptomics, proteomics, and metabolomics could facilitate a better understanding of the interaction between C. orbiculare effectors and host resistance genes in the already sequenced watermelon genome. In this review, we encompass and discuss (i) the history of watermelon anthracnose, taxonomy, morphology, and diversity in races of C. orbiculare; (ii) the epidemiology of the anthracnose disease and host resistance; (iii) the genetics behind the pathogenesis; and (iv) the current advances in breeding and molecular efforts to elucidate anthracnose resistance.