Clinical conditions commonly associated with abnormal uterine activity are preterm labour (PTL), dysfunctional labour and post partum haemorrhage (PPH). Preterm birth is the biggest cause of neonatal mortality and morbidity. Dysfunctional labour leads to operative vaginal and abdominal delivery with its inherent maternal risks, and PPH is a major global cause of maternal morbidity and mortality accounting for around 25% of deaths in postpartum mothers in developing nations. PTL, PPH and dysfunctional labour have complex, multi-factorial aetiologies and it is unrealistic to assume that all cases will be treated by a single approach. None-the-less a greater understanding of the underlying principles of uterine contractions offers the prospect of discovering novel therapeutics for these disorders. We have established a research programme combining molecular biology, computational modeling, in vitro and in vivo physiology, and drug discovery to increase basic understanding and discover new treatments. In this presentation I shall argue that such an approach has enormous potential by using our discovery of a novel inwardly rectifying potassium channel as an exemplar. To identify novel targets we started by using laser capture micro dissection to isolate mRNA from pure myometrial (MSMC) and vascular smooth muscle cells (VSMC) present in uterine samples taken at cesarean section. mRNA was then amplified and sequenced by RNAseq. Gene lists of all expressed ionic conductances were constructed and analysed for significant differences between MSMC and VSMC. Identified candidates were then subjected to a ‘virtual’ screen by computationally modeling the effect of changing channel densities/activity based on known biophysics (Aslanidi et al. 2011). One candidate, Kir7.1 was taken forward as a potential modifier of resting membrane potential and uterine excitability during gestation. qRT-PCR and western blot analysis demonstrated that Kir7.1 expression is regulated at the mRNA and protein level during gestation in mouse and human. Knockdown of Kir7.1 protein, in vitro, by lentiviral miRNA resulted in profoundly increased contractions when compared to scrambled control. Over expression of hKir7.1 resulted in inhibition of phasic contractions. Microelectrode recordings of phasic contractions in knockdown and overexpressing strips demonstrated that the observed phenotypes were mediated by a change in membrane potential. In vivo, mice injected with lentiviral miRNA demonstrated significantly increased intrauterine pressure and preterm delivery when compared to scrambled control. To explore potential therapeutic avenues at this protein target we tested the effect of the novel Kir7.1/ROMK inhibitor VU590 and VU590 (Lewis et al. 2009) like derivatives on whole cell current under voltage clamp conditions combined with current clamp recordings of in vitro contracting myometrial strips. VU590 dose dependently inhibits a Kir7.1 like current in native mouse and human MSMC, whilst addition of VU590 to contracting myometrial strips leads to rapid depolarization of resting membrane potential followed by long-lasting tonic contractions that are reversible on washout. To test whether physiological activity was specific to Kir7.1 we manufactured chemical derivatives that lost Kir7.1 activity but retained ROMK activity. These derivatives failed to affect contractions or membrane potential. I shall conclude that genomic screening of laser-dissected tissues, taken under different physiological conditions, and combined with RNAseq is an effective means of surveying mRNA profiles. Such profiles, when combined with accurate biophysical information and computational models can lead to a rapid, predictive, focusing down on potential targets with desirable physiological phenotypes. Once identified, in vitro knockdown of targets using lentiviral delivery vectors provides an excellent first means to assess whether subsequent investment of time and resources in a drug discovery programme is worthwhile.