With the recent findings of genetic causes of cholestasis (see Chapter 14), many of the previously ascribed “indeterminate” forms of cholestasis have been assigned molecular forms of causality because of specific impairments in critical genes involved in the formation of bile. In a similar vein, exploration of the effects of various endogenous and exogenous factors on the expression and function of these same essential bile formation genes has led to a greater molecular understanding of acquired forms of cholestasis. Thus, within the past 5–10 years, it has become possible to tease apart not only the means by which the liver is damaged by rare single-gene defects in critical hepatobiliary genes, but also how these gene products are engaged in the response and adaptation to cholestasis, and intriguingly, why these processes may not be fully adequate to protect the liver. In particular, see Chapter 14 and recent references [1–6] for our increasing knowledge of the expression, structure, and regulation of these genes and gene products in the underlying processes that lead to cholestasis. Among the more relevant findings has been that the processes of bile formation, cholestasis, and adaptation are inherently intertwined with structural, developmental, biochemical, intercellular communication, subcellular organization, cell signaling pathways, and physiologic components of the liver and liver function. In this chapter, attention focuses upon the basic mechanisms of bile formation as well as the genetic and acquired pathways that lead to cholestasis.