Negative symptoms of schizophrenia have often been associated with poor functional outcome and poor response to antipsychotic treatment. Studies reporting drug induced significant reduction of negative symptoms after treatment actually refer to negative symptoms secondary to positive, depressive and/or extrapyramidal symptoms. Negative symptoms that do not improve following antipsychotic treatment represent a real challenge for future development of effective treatments. Two approaches have been so far proposed to improve research on these negative symptoms. The first one is based on the identification of primary and enduring negative symptoms, that characterize a schizophrenia subtype known as deficit schizophrenia (DS). The prevalence of DS is 15%–20% in population based samples, but tends to be much lower in first-episode patients. Individuals with DS have worse long-term outcome and poorer response to antipsychotics than those with other forms of schizophrenia. The second approach is based on the identification of persistent negative symptoms, which are likely to be primary, but may be secondary. Few data are available on the prevalence of persistent negative symptoms in patients with schizophrenia. In first episode subjects from the EUFEST study 11% of the study sample showed persistent negative symptoms (PNS). They had poorer functional outcome and lower remission rates than those without PNS after 1 year of treatment. Research on clinical and biological correlated of primary and/or persistent negative symptoms might help in reducing schizophrenia heterogeneity and developing new treatments.