Current findings of neighboring genes involved in plant specialized metabolism provide the genomic signatures of metabolic evolution. Two such genomic features, namely, (i) metabolic gene cluster and (ii) neo-functionalization of tandem gene duplications, represent key factors corresponding to the creation of metabolic diversity of plant specialized metabolism. So far, several terpenoid and alkaloid biosynthetic genes have been characterized with gene clusters in some plants. On the other hand, some modification genes involved in flavonoid and glucosinolate biosynthesis were found to arise via gene neo-functionalization. Although the occurrence of both types of metabolic evolution are different, the neighboring genes are generally regulated by the same or related regulation factors. Therefore, the translation-based approaches associated with genomics, and transcriptomics are able to be employed for functional genomics focusing on plant secondary metabolism. Here, we present a survey of the current understanding of neighboring genes involved in plant secondary metabolism. Additionally, a genomic overview of neighboring genes of four model plants and transcriptional co-expression network neighboring genes to detect metabolic gene clusters in Arabidopsis is provided. Finally, the insights functional genomics have provided concerning the evolution and mechanistic regulation of both the formation and operation of metabolic neighboring clusters is discussed.