A progressive depression in the in vitro hepatic microsomal enzyme metabolism of drug substrates, during pregnancy in the Wistar rat, was measured against various parameters. This depression was greatest with aniline para-hydroxylation and least with p-nitrobenzoic acid reduction. The depressed metabolism, which correlated with prolonged in vivo hexobarbital sleeping times, was paralleled by falls in hepatic microsomal cytochrome P-450 levels. There was a rapid reversal of this depression just before delivery, but these changes did not appear to be controlled by progesterone levels. The suggestion is advanced that the lower levels of hepatic microsomal enzyme activity might reflect a biological control mechanism to ensure the elevated levels of progesterone required to maintain the pregnant state. The relationship between changes in liver weight and enzyme activity was also examined as a possible explanation of the observed depression in drug metabolism during pregnancy.