Predicting prognosis and identifying the line of differentiation in gastrointestinal stromal tumors (GIST) have been problematic. The first part of this review briefly summarizes ultrastructural studies and then focuses on the many immunohistochemical studies of cellular differentiation in GIST. The second part reviews pathologic evaluation of GIST from the perspective of risk assessment. A scheme is proposed for segregating GIST into groups with low and high risk for aggressive clinical behavior.