Persistent negative symptoms represent an alternative approach for assessing negative symptoms in the context of clinical trials. Persistent negative symptoms are designed to capture those symptoms that lead to functional impairment but are currently understudied and for which there are no currently available effective treatments. Persistent negative symptoms differ from the 2 most commonly used approaches: primary, enduring negative symptoms or deficit symptoms and negative symptoms broadly defined to include negative symptoms, regardless of their etiology or duration. In contrast to deficit symptoms, persistent negative symptoms may include secondary negative symptoms. However, in contrast to negative symptoms broadly defined, the secondary negative symptoms included in the assessment of persistent negative symptoms only include those that have failed to respond to usual treatments for secondary negative symptoms. In consequence, the presence of persistent negative symptoms identifies a patient population with clinically relevant symptomatology, which is larger than the one with the deficit syndrome but less heterogeneous than that captured through the use of a nonrestrictive definition of negative symptoms. This may facilitate the selection of subjects for inclusion into research and efforts to develop new pharmacological treatments and enhance our understanding of a relevant clinical problem. Ultimately, the investigation of the different entities characterized by negative symptoms, such as persistent negative symptoms, and the enhanced understanding of their biological and clinical characteristics may help to unravel the psychopathological and biological heterogeneity of schizophrenia.