Cotton has long been known as a fiber plant. Besides the cotton fiber, the cottonseed oil and cottonseed protein are two other major products of cotton plants. However, the applications of the cottonseed oil and protein are limited because of the presence of toxic gossypol, which is unsafe for human and monogastric animal consumption. Meanwhile, gossypol in cotton increases the plant defense response to insect herbivores and pathogens. Consequently, gossypol has been extensively used in clinical trials in biomedical science. Over the last few years, major advances have occurred in both understanding and practice with regard to molecular regulation of gossypol pathway in cotton plant or hairy root culture. This review highlights a few major recent and ongoing developments in metabolic engineering of gossypol, as well as suggestions regarding further advances needed.