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A deficiency in both <jats:styled-content style=\"fixed-case\">MK<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">PTN<\/jats:styled-content> has been suggested to be an important genetic factor, which confers vulnerability to the development of the neurodegenerative disorders associated with drugs of abuse in humans. In this review, evidence demonstrating that <jats:styled-content style=\"fixed-case\">MK<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">PTN<\/jats:styled-content> limit the rewarding effects of drugs of abuse and, potentially, prevent drug relapse is compiled. There is also convincing evidence that <jats:styled-content style=\"fixed-case\">MK<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">PTN<\/jats:styled-content> have neuroprotective effects against the neurotoxicity and development of neurodegenerative disorders induced by drugs of abuse. Exogenous administration of <jats:styled-content style=\"fixed-case\">MK<\/jats:styled-content> and\/or <jats:styled-content style=\"fixed-case\">PTN<\/jats:styled-content> into the <jats:styled-content style=\"fixed-case\">CNS<\/jats:styled-content> by means of non\u2010invasive methods is proposed as a novel therapeutic strategy for addictive and neurodegenerative diseases. Identification of new molecular targets downstream of the <jats:styled-content style=\"fixed-case\">MK<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">PTN<\/jats:styled-content> signalling pathways or pharmacological modulation of those already known may also provide a more traditional, but probably effective, therapeutic strategy for treating addictive and neurodegenerative disorders.<\/jats:p><\/jats:sec><jats:sec><jats:title>Linked Articles<\/jats:title><jats:p>This article is part of a themed section on Midkine. 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