The first phase of the CNTRICs initiative focused on the identification of cognitive constructs from human and animal neuroscience that were relevant to understanding cognitive deficits in schizophrenia, as well as promising task paradigms that could be used to assess these constructs behaviorally. The current phase of CNTRICs has the goal of expanding this initial work by including measures of brain function that can augment these behavioral tasks as biomarkers to be used in the drug development processing. Here we review many of the psychometric issues that need to be addressed in regards to the development and inclusion of such methods in the drug development process. In addition, we review quality assurance concerns, issues associated with multi-center trials, concerns associated with potential pharmacological confounds on imaging measures, as well as power and analysis considerations. Although review is couched in the context of the use of biomarkers for treatment studies in schizophrenia, we believe the issues and suggestions included are relevant to the entire range of neuropsychiatric disorders as well as to a wide range of imaging modalities (i.e., fMRI, PET, ERP, EEG, TMS, NIR, etc.), and are relevant to both pharmacological and psychological intervention approaches.