Large datasets that enable researchers to perform investigations with unprecedented rigor are growing increasingly common in neuroimaging. Due to the simultaneous increasing popularity of open science, these state-of-the-art datasets are more accessible than ever to researchers around the world. While analysis of these samples has pushed the field forward, they pose a new set of challenges that might cause difficulties for novice users. Here, we offer practical tips for working with large datasets from the end-user’s perspective. We cover all aspects of the data life cycle: from what to consider when downloading and storing the data, to tips on how to become acquainted with a dataset one did not collect, to what to share when communicating results. This manuscript serves as a practical guide one can use when working with large neuroimaging datasets, thus dissolving barriers to scientific discovery.