This chapter is a review of knowledge to-date on striosome and matrix pathology in Huntington disease (HD). Inhomogeneous biochemical organization in the neostriatum was first identified by Pert et al (1975, 1976) and Atweh and Kuhar (1977), who described p-opiate receptor-rich patches in rat neostriatum. Striosomes in human neostriatum were first defined by Graybiel and Ragsdale (1978) as acetylcholinesterasepoor islands embedded within the acetylcholinesterase-rich matrix. It was later found that the two systems overlapped (Graybiel et al, 1981; Herkenham and Pert, 1981). Soon after, it was shown that the matrix and striosome compartmentation was demonstrable by immunocytochemistry using antibodies against the calcium-binding protein calbindin (Gerfen et al, 1985). The striosomal system has many other biochemical differences from the matrix (Holt et al, 1997). Striosomal connections differ from those of the matrix (Donoghue and Herkenham, 1986; Graybiel, 1990; Gerfen, 1992; Joel and Weiner, 2000). Striosomes receive cortical input primarily from limbic cortical areas and send axons primarily to the pars compacta of the substantia nigra, whereas the matrix receives most cortical input from non-limbic regions and sends its output axons to the two segments of the globus pallidus and the pars reticulata of the substantia nigra. About half of matrix neostriatal medium spiny neurons contain enkephalin in addition to GABA and send their axons primarily to the lateral pallidal segment, and the other half contain substance P in addition to GABA and send their axons to the internal pallidal segment and to the substantia nigra. atology.