The advent of the use of in vivo microdialysis and voltammetry techniques in behaving animals has ushered in a great deal of research on the neurochemistry of cognition. While studies exploring the relationship between neurotransmitter release and cognitive processing are quite feasible, a number of methodological and conceptual issues pose challenges to the interpretation of experimental results. These challenges include: 1) a demonstration that the behavioral task highlights the particular cognitive construct under study; 2) a determination of the role of non-cognitive variables (i.e. transfer effects, sensory stimulation, motivational variables, and motor activity) in affecting transmitter release, and 3) a recognition of the value of a distributed systems approach to studying the neurochemistry of cognition. This review summarizes the data on the validity of microdialysis and voltammetry as correlates of neurotransmitter release and then illustrates the impact that the above challenges can have on the conclusions drawn from various studies.