The immune system keeps the host body safe and protected from diseases. Genetic diseases can often manipulate the immune genes at genetic levels so that the proteins in charge of ensuring the protection cannot do their job correctly. Such manipulation can come in various ways. In this chapter, emphasis will be put on how polymorphisms can contribute to the development, progression, and severity of cancer. Different polymorphisms like insertions, deletions, repeat number variations, and even single-nucleotide polymorphisms can lead to an unprotective function of the immune system. A healthy host can eliminate any abnormal cell, such as cancer, by using its robust and highly efficient immune system. However, when the immune system cannot recognize the abnormality within the host, or when cancer cells make a way to evade the immune action, the condition worsens. Ultimately, the patient starts to go toward a fatal disease. Being able to clearly understand all the possible associations of genes and genetic variants for a particular cancer type can assist in the early detection and development of specific drugs with enhanced sensitivity and even enable humans to take protective actions. Therefore, polymorphisms and association studies are crucial for all genetic diseases, including cancer.