While current treatments for schizophrenia often provide much relief for positive symptoms such as hallucinations, other symptoms, particularly cognitive deficits, persist and contribute to substantial suffering and reduced quality of life for patients. In searching for novel therapeutic avenues to treat cognitive deficits in schizophrenia, recent work is exploring nicotinic receptor neurobiology. Supported by a large body of evidence, with contributions from studies of smoking behaviors, genetics, receptor distribution and function, animal models and nicotinic effects on illness symptoms, the alpha7 nicotinic receptor has emerged as a potential therapeutic target. Despite promise in early clinical trials, however, no drug targeting nicotinic systems has succeeded in larger phase 3 trials. Following a brief review of nicotinic receptor biology and the evidence that has led to pursuit of alpha7 nicotinic agonism as a therapeutic strategy, this review will provide an update on the status of recent trials, discuss potential issues that may have contributed to negative outcomes, and point to new directions and promising advances in developing alpha7 nicotinic receptor-based treatment for cognitive symptoms in schizophrenia.By examining alpha7 nicotinic receptor biology and recent efforts to target the receptor in clinical trials, it is hoped that investigators will be motivated to explore novel, promising directions focusing on the receptor as a strategy to treat cognitive symptoms in schizophrenia.