Machine learning methods may have the potential to significantly accelerate drug discovery. However, the increasing rate of new methodological approaches being published in the literature raises the fundamental question of how models should be benchmarked and validated. We reanalyze the data generated by a recently published large-scale comparison of machine learning models for bioactivity prediction and arrive at a somewhat different conclusion. We show that the performance of support vector machines is competitive with that of deep learning methods. Additionally, using a series of numerical experiments, we question the relevance of area under the receiver operating characteristic curve as a metric in virtual screening. We further suggest that area under the precision-recall curve should be used in conjunction with the receiver operating characteristic curve. Our numerical experiments also highlight challenges in estimating the uncertainty in model performance via scaffold-split nested cross validation.