Biotic and abiotic stresses negatively affect the yield and overall plant developmental process, thus causing substantial losses in global sweet potato production. To cope with stresses, sweet potato has evolved numerous strategies to tackle ever-changing surroundings and biological and environmental conditions. The invention of modern sequencing technology and the latest data processing and analysis instruments has paved the way to integrate biological information from different approaches and helps to understand plant system biology more precisely. The advancement in omics technologies has accumulated and provided a great source of information at all levels (genome, transcript, protein, and metabolite) under stressful conditions. These latest molecular tools facilitate us to understand better the plant’s responses to stress signaling and help to process/integrate the biological information encoded within the biological system of plants. This review briefly addresses utilizing the latest omics strategies for deciphering the adaptive mechanisms for sweet potatoes’ biotic and abiotic stress tolerance via functional genomics, transcriptomics, proteomics, and metabolomics. This information also provides a powerful reference to understand the complex, well-coordinated stress signaling genetic regulatory networks and better comprehend the plant phenotypic responses at the cellular/molecular level under various environmental stimuli, thus accelerating the design of stress-resilient sweet potato via the latest genetic engineering approaches.