The epithelial lining of the intestine is constantly exposed to a hostile environment containing a mixture of gastric acids, consumed harmful substances and microbes. It is widely accepted that the intestine has multiple mechanisms to protect itself against tissue damage. Here, we review three cellular protection mechanisms that protect intestinal tissue against accumulation of somatic mutations: the conveyer belt-like structure, stem cell competition and crypt fusion. We highlight the events that can perturb these cellular protection mechanisms, and their impact on accumulation of new (oncogenic) mutations. Lastly, we review the potential of in-vitro and intravital microscopy techniques to study the dynamics of these protection processes. These studies may identify new targets that can be used to manipulate cellular protection mechanisms in such a way that accumulation of new mutations can be reduced. Importantly, reducing mutation accumulation has the potential to delay aging, and the initiation and progression of diseases such as colorectal cancer.