Various factors that negatively influence male fertility can affect sperm morphology and physiology. Many studies on humans and animals suggest that both radiation and chemotherapy alter the sperm chromatin, inducing significant damage to sperm DNA, and decrease the level of protamination, thereby altering DNA compaction. Spermatozoa from cancer survivors are affected by chemotherapy even years after the end of treatment. We are exposed to various toxicants present in the environment (e.g., products of air pollution, pesticides, and plasticizers) whose impact on human male reproduction has not yet been established.This chapter aims to update our knowledge on how the sperm chromatin structure is modified by external agents and to describe the different strategies available to better study this complex structure in infertile men.