Background <p>Signature production represents a complex motor and cognitive behavior, highly automatized and repeated countless times throughout life. It ranks among the most durable graphic forms, often preserved even when writing processes are impaired. Studies examining signature characteristics in clinical cohorts are limited. The available evidence raises questions about its potential as a behavioral marker of neurological and psychiatric disorders.</p> Methods <p>We conducted a PRISMA-compliant systematic review up to 4th December 2025 to summarize evidence on how neurological and psychiatric conditions may affect signature features. Eligible articles on this topic were searched in Scopus, Web of Science, and PubMed databases. Sixteen papers were included, and their results were systematically described and qualitatively analyzed.</p> Results <p>The available literature suggests that signature production appears relatively independent of global cognitive decline, although it is sensitive to specific pathological conditions (e.g., micrographia in Parkinson’s disease, increased tortuosity in cerebral small vessel disease, and alterations observed in mania, delirium, obsessive-compulsive disorder, and major depressive disorder). Alterations commonly affect kinematic parameters, as well as visuospatial and constructional features. However, no disorder-specific signature pattern emerges from current evidence, largely due to the methodological heterogeneity across studies.</p> Conclusions <p>The handwritten signature holds promise as a behavioral marker of brain disorders, serving as a potentially useful, complementary - rather than a stand-alone - indicator of neurological and psychiatric conditions, which could be potentially useful in clinical settings. The implications for forensic applications remain largely theoretical and have not yet been standardized.</p>