Cognitive deficits are a core feature of schizophrenia. The association between cognitive deficits and poor functional outcome suggest that treatment of cognitive deficits may lead to important functional improvements. However, there are many key components to the methodology of cognitive enhancement clinical trials that must be addressed. This chapter discusses various design features of cognitive enhancement clinical trials for patients with schizophrenia, including inclusion criteria, baseline medication status, baseline level of cognitive impairment, sample size consideration, trial duration, test batteries, and the use of co-primary non-performance measures of cognition with ecological validity.