Gonadal-derived inhibins are essential factors in mammalian reproduction, negatively regulating follicle stimulating hormone (FSH) production by gonadotrope cells of the anterior pituitary. Inhibins (α/β-heterodimers) modulate gonadotrope function by antagonizing the actions of the related proteins, activins (β/β homodimers), at the level of the receptor. Expression of the inhibin α-subunit is essential in restricting both the production and activity of activin β/β-dimers, as genetic deletion of the inhibin α-subunit in mice results in a pathological increase in activins. Indeed, activin levels are elevated as much as 500-fold in inhibin α-subunit deficient mice, inducing gonadal tumour formation and lethal cachectic wasting. Consequently, inhibin knockout mice, which have been the only model available for the past 25 years, do not actually reflect a loss of inhibin activity, but rather a pathological increase in activin levels. Here, we describe a new inhibin mutant mouse model to study inhibin physiology. We used the CRISPR/Cas-9 system to introduce a single inactivating mutation into inhibin in C57/Bl6 mice. This point mutation ablated inhibin bioactivity, without the accompanied pathological increase in activin production. Consequently, the mice did not develop gonadal tumours, nor the cachectic wasting that compromised inhibin α-subunit knock-out mice. In response to inhibin inactivation, activin activity was unopposed, resulting in elevated levels of circulating FSH in both male and female mice. Elevated levels of FSH in female mutant inhibin mice resulted in a doubling in ovarian weights, and histological analysis indicated that this was due to increased numbers of corpora lutea and large antral follicles. In contrast, testis weights and spermatogenesis appeared to be normal in mutant male inhibin mice. Current studies aim to determine the impact of inhibin inactivation on the establishment and maintenance of pregnancy. Our new inhibin mouse will allow for the first accurate characterisation of the physiological roles of inhibins.