The end of the last millennium witnessed an unprecedented degree of public awareness regarding mental disorder as well as motivation for policy change. Like Sartorius, we contend that the continued stigmatization of mental illness may well be the central issue facing the field, as nearly all attendant issues (e.g., standards of care, funding for basic and applied research efforts) emanate from professional, societal, and personal attitudes towards persons with aberrant behavior. We discuss empirical and narrative evidence for stigmatization as well as historical trends regarding conceptualizations of mental illness, including the field's increasing focus on genetic and neurobiological causes and determinants of mental disorder. We next define stigma explicitly, noting both the multiple levels (community, societal, familial, individual) through which stigma operates to dehumanize and delegitimize individuals with mental disorders and the impact of stigma across development. Key developmental psychopathology principles are salient in this regard. We express concern over the recent oversimplification of mental illness as “brain disorder,” supporting instead transactional models which account for the dynamic interplay of genes, neurobiology, environment, and self across development and which are consistent with both compassion and societal responsibility. Finally, we consider educational and policy-related initiatives regarding the destigmatization of mental disorder. We conclude that attitudes and policy regarding mental disorder reflect, in microcosmic form, two crucial issues for the next century and millennium: (a) tolerance for diversity (vs. pressure for conformity) and (b) intentional direction of our species' evolution, given fast-breaking genetic advances.