Cancer generally begins with a genetic mutation that allows normal and healthy cells to continue growing without responding to the signals to stop, which normal cells do. Cancer cells continue to grow, eventually multiplying out of control. The accumulating abnormal cells eventually end up forming a mass or a tumor.

Neuroblastoma begins in neuroblasts, which are immature nerve cells that form on a fetus as part of its development process. As the fetus matures, neuroblasts turn into nerve cells and fibers as well as the cells making up the adrenal glands. Most neuroblasts mature by birth, but sometimes a small number of immature neuroblasts are found in newborns. In most cases, these neuroblasts mature or eventually disappear within some time. Others, however, form a tumor, which is termed neuroblastoma.

The initial genetic mutation that leads to neuroblastoma is still unknown.

Several lifestyle factors like body weight, physical activity, diet, and tobacco use are known to play a major role in several types of cancers. These factors, however, take many years to influence cancer risk, and therefore, they are not considered to play much of a role in childhood cancers, like neuroblastomas.

There are also no environmental factors are known to increase the chance of getting neuroblastoma.

Children who have the familial form of neuroblastoma, usually come from families having one or more members who have had neuroblastoma as infants.

Children having familial neuroblastoma can sometimes develop two or more of these cancers in different organs. For example, they can develop it in both adrenal glands or in more than one sympathetic ganglion.

According to certain studies, children with birth defects might have an increased risk of developing neuroblastoma. It is possible that some of the links between birth defects and neuroblastoma might be related to changes in genes that happen during fetal development.