Controlled uterine smooth muscle activity is essential for successful childbirth. Unfortunately, problems with uterine contractions, either elicited prematurely, or being of inappropriate strength, are quite common and remain a cause of maternal and neonatal morbidity, and an obstetrical challenge. There is a lack of knowledge of basic mechanism controlling uterine contractility, and to increase our knowledge and uncover mechanisms leading to uterine function and dysfunction is a physiological challenge. Perhaps the most fundamental question to be addressed in uterine physiology and pathophysiology is, how is the electrical activity that triggers and modifies contraction initiated? This is a question that can be posed at several levels; is there a special type of cell within the myometrium that acts as a pacemaker? What are the properties of pacemaker cells, e.g. ion channels expressed? What are the roles of local and global Ca²⁺ signals in producing this excitation? How is the excitation spread to other cells? How do agonists, intracellular signalling pathways and local factors, such as pH, influence excitability? What changes occur in these mechanisms and properties within normal labour, and what happens in pre-term and dysfunctional labours? A daunting list. I will present data that give us some insight into some of these questions. Recent studies of freshly dispersed myometrial cells from humanely killed pregnant rats have found that identical looking myocytes differ markedly in their ability to generate Ca²⁺ spikes, fire action potentials and produce outward current and thus under identical conditions healthy myocytes differ in their spontaneous activity. They also differ in the ion channels they express, e.g. in a study of inward current produced by Ca-activated Cl- (Cl_Ca) channels in rat myometrium, we found that only around 30% of cells (n>300) had a Cl_Ca current. Expression of such inward currents would be consistent with a pacemaking potential in these cells and their pharmacological inhibition produced a decrease in the frequency of uterine Ca2+ transients and contractions. In addition, we have recently examined cells from freshly dispersed human and rat uterus and in situ preparations, and discovered numerous interstitial-like cells (ILCs). These were multi-polar cells with spider-like projections and enlarged central regions. They were non-contractile, vimentin-positive and had numerous caveolae and mitochondria. Electron-microsopy of in situ preparations showed them making close contact with many myocytes and axons. Their role remains to be elucidated. The role of local sub-cellular Ca²⁺ signals e.g. Ca²⁺ sparks and puffs from the sarcoplasmic reticulum (SR) is virtually unknown in uterine smooth muscle. In other smooth muscles much progress has been made in investigating these events and relating them to excitability and contraction. All three isoforms of both the ryanodine receptor (RyR) and IP₃ receptor have been reported in human myometrium, but there is species variation e.g. mouse has only RyR3. There has been no investigation in myometrium of the nature and role of local Ca²⁺ signals, and their relation to global Ca²⁺ signals, e.g. Ca²⁺ waves and transients, is unclear. Similarly although Ca-activated K channels (BK) have been demonstrated in the myometrium, the role of SR Ca²⁺ release vs. Ca²⁺ entry in activating the channels is unknown. I will discuss two recent studies where we have data which link lab and clinical studies. Our in vitro studies had shown an inhibitory effect of acidic pH on uterine excitability and contractility. We therefore undertook a study of myometrial capillary pH in women suffering dysfunctional labour. Blood was taken at the first uterine incision in women having a Caesarean section (CS) either electively or as a consequence of fetal distress or dysfunctional labour. The results were startling and significant. The pH of myometrial capillary blood from women having a dysfunctional labour was significantly lower, at 7.35, than that from any other group. Furthermore lactate was higher and capillary oxygen saturation was lower. These data support the hypothesis that myometrial blood is more acidic in women labouring dysfunctionally, in a manner consistent with hypoxic episodes. We also determined that the pH drop determined in vivo, was sufficient in vitro, to change a normal pattern of uterine contractility into a dysfunctional one. In another set of experiments we have found that, in vitro, elevated cholesterol is deleterious to force and Ca²⁺ signalling in the myometrium. In a parallel study we have found that obese pregnant women, who have elevated cholesterol levels also are significantly more likely than lean women to suffer a dysfunctional labour, due to poor contractions. We are currently looking further into the mechanisms of both these exciting findings.