Proper tissue fixation is essential to ensure the highest level of specimen evaluation. Pathologists and laboratory staff are frequently consulted by clinical counterparts regarding what fixative should be used for different tissues or to enable a diagnosis of a specific condition. It is vital for the patient that the pathologist provides accurate information to ensure proper fixation. Frequently, once a tissue has been fixed inadequately or inappropriately, remedial changes may no longer be possible. Most often formalin is an adequate choice, if not the optimal one; however, there are certain situations when placing the tissue in formalin may limit the ability to reach a definitive diagnosis. It is imperative for pathologists to have the knowledge to communicate which fixative is optimal. Furthermore, as we move into a world of personalized medicine, where ancillary testing has both diagnostic and specific therapeutic implications, knowledge about how different fixatives affect immunohistochemistry, cytogenetics, and molecular studies becomes even more significant. This chapter provides practical information regarding common fixatives, their mechanism of action and optimal uses.