The overexpression of a single tyrosinase gene can induce conspicuous pigmentation in nonpigmented cells. We hypothesized that some unknown tyrosinase-associated genes are simultaneously regulated by melanin synthesis. To improve understanding of melanogenesis and tyrosinase-associated functions, we attempted to profile the genes that are altered during melanin production in HEK293 cells by using a functional DNA chip microarray. The candidate genes were obtained based on significance analysis of microarray (SAM) and further computational prediction via protein-protein interaction (PPI) mapping suggested that newly detected hub genes were involved in melanogenesis. PPI mapping using bioinformatic tools revealed 8 genes that formed an interaction hub. The yeast two-hybridization results suggested some candidate genes could interact with tyrosinase. The present study provides information to further understand the complex factors associated with tyrosinase-induced melanogenesis and apoptosis. The approach of combining expression data analysis and predicted protein interaction partners can help identify genes involved in pigmentation.