The generally improved understanding of biochemical pathways and genetic alterations that underlie many disease processes have led medical scientists to rely increasingly on the identification of specific molecular markers that are important for diagnosis and management of diseases. This molecular approach requires optimal preservation of proteins, RNA, and DNA in diagnostic specimens of tissue. However, the standard tissue preparation designed for optimum histomorphological examination constitutes several steps, none of which aims at good recovery of protein, RNA, or DNA. This article reviews the more complex issues of fixation, including the effects of fixation on immunohistochemistry and recovery of RNA, DNA, and proteins from fixed tissue. We also discuss over- and underfixation, microwave fixation, perfusion-fixation, and the potential reversibility of molecular changes induced by formaldehyde and other fixatives. We stress the need for designing fixatives rationally so that their effects are known and could be controlled and reversed when needed.