Estradiol and progesterone vary along the menstrual cycle and exert opposite effects on a variety of neurotransmitter systems. However, few studies have addressed menstrual cycle-dependent changes in the brain. In the present study we investigate menstrual cycle changes in brain activation and connectivity patterns underlying cognition. Thirty-six naturally cycling women underwent functional MRI during two cognitive tasks: spatial navigation and verbal fluency. While no significant performance differences were observed along the menstrual cycle, the changes in brain activation patterns are strikingly similar during both tasks. Irrespective of the task, estradiol boosts hippocampal activation during the pre-ovulatory cycle phase and progesterone boosts fronto-striatal activation during the luteal cycle phase. Connectivity analyses suggest that the increase in right-hemispheric frontal activation is the result of inter-hemispheric decoupling and is involved in the down-regulation of hippocampal activation.