The constitutively active, atypical protein kinase C, protein kinase M-ζ (PKMζ), is exclusively expressed in the brain and its expression increases following exposure to drugs of abuse. However, the limitations of currently available tools have made it difficult to examine the role of PKMζ in cocaine self-administration and relapse. The current study demonstrates that constitutive deletion of PKMζ potentiates cue-induced reinstatement of cocaine seeking and increases both food and cocaine self-administration, without affecting cue-driven food seeking in both male and female mice. Conditional deletion of PKMζ within the nucleus accumbens recapitulated the increase in cocaine taking and seeking seen in the constitutive knockout mice, but only in male animals. Site-specific knockdown of PKMζ in the nucleus accumbens had no effect on cocaine taking or seeking in female mice. Additionally, neither male nor female mice exhibited any alterations in food self-administration or cue-induced reinstatement of food seeking following accumbal deletion of PKMζ. Taken together these results indicate that PKMζ may act to dampen cocaine taking and seeking. Furthermore, these results indicate that PKMζ is playing divergent roles in reward seeking in males and females.