The debate on the causes of cancer, whether it is due to genomic instability or impaired energy metabolism, is ongoing. Research has indicated that the carcinogenic process may not be solely driven by the accumulation of random gene mutations but rather by a mitochondrial metabolic disease (Seyfried, Front Cell Dev Biol 3:43, 2015). However, the factors that trigger the metabolic reprogramming of cancer cells remain unclear. Further research is required to elucidate the causal relationship between metabolic abnormalities and gene mutations, as well as the ability of mutations to induce metabolic abnormalities. Nicotinamide adenine dinucleotide (NAD+) is a coenzyme for redox reactions and a crucial component of energy metabolism. It also plays a vital role as an auxiliary factor or substrate for NAD+-dependent non-redox enzymes, such as the sirtuin family, poly (ADP-ribose) polymerase (PARP) family, and cluster of differentiation 38 (CD38) and CD157. NAD+ directly or indirectly influences several critical cellular functions, including metabolic pathways, DNA repair, chromatin remodeling, cell growth, immune response, and apoptosis, all of which are essential for maintaining metabolic dynamic homeostasis and cellular health. Given the significant role of NAD+ in cell metabolism and signaling, this chapter aims to explore the importance of NAD+ in the onset, progression, metastasis, and treatment of tumors from diverse perspectives.