Reducing attrition rates remains a major challenge in drug development, with the probability of a drug candidate successfully completing Phase II trials currently estimated at only 34%. The physicochemical properties of small-molecule drug candidates are one important factor influencing the chance of success and, importantly, are under the control of medicinal chemists. In their Review, Cummings and colleagues discuss the use of chemical predictive modelling tools — such as quantitative structure–activity relationships — to help guide the selection and optimization of compounds and the challenges associated with their application. Meanwhile, our two other Reviews this month focus on novel anticancer strategies. First, Helin and colleagues discuss the role of histone methylation in the post-translational regulation of gene expression, focusing on the functions of histone lysine methylase enzymes. They present recent evidence supporting a role for members of the lysine-specific demethylase and the Jumonji domain-containing demethylase families in cancer development, highlighting emerging small-molecule inhibitors. Second, Mak and colleagues consider the role of oxidative stress in tumorigenesis and discuss the ability of cancer cells to balance their characteristically high levels of reactive oxygen species with enhanced antioxidant defence mechanisms. They highlight the key cellular sensors and modulators of oxidative stress while assessing the potential to therapeutically target the antioxidant capacity of tumour cells. Finally, in their Perspective, Bloechl-Daum and colleagues discuss the challenges faced by regulatory agencies in determining an appropriate balance between benefit and risk with the limited data that are typically available before drug approval. The adverse effects of regulatory risk-aversion and strategies to better align acceptance of risk and uncertainty by regulators with the interests of public health are presented.