Discovered more than four decades ago, nonsense-mediated mRNA decay (NMD) plays a fundamental role in the regulation of gene expression and is a major contributor to numerous diseases. With advanced technologies, several novel approaches aim to directly circumvent the effects of disease-causing frameshift and nonsense mutations. Additional therapeutics aim to globally dampen the NMD pathway in diseases associated with pathway hyperactivation, one example being Fragile X syndrome. In other cases, therapeutics have been designed to hijack or inhibit the cellular NMD machinery to either activate or obviate transcript-specific NMD by modulating pre-mRNA splicing. Here, we discuss promising approaches employed to regulate NMD for therapeutic purposes and highlight potential challenges in future clinical development. We are optimistic that the future of developing target-specific and global modulators of NMD (inhibitors as well as activators) is bright and will revolutionize the treatment of many genetic disorders, especially those with high unmet medical need.