Due to advances in both public health and healthcare, there is a growing population of older people living with multimorbidity and polypharmacy. Optimising medication therapy for older adults has thus become more complex. Qualitative work with healthcare professionals indicates that prescribing for this population is considered complex and challenging. In addition, older people living with multimorbidity and polypharmacy have identified medicine management as an area of concern. This population is often excluded from intervention studies assessing the effectiveness of medications, meaning there is also uncertainty around the potential risks and benefits of therapy. It is thus unsurprising that older people, particularly those with polypharmacy, are at increased risk of preventable drug-related morbidity. Various approaches have been undertaken to both describe and address this problem. Explicit and implicit prescribing criteria have been developed and utilised for pharmaco-epidemiological studies to describe and characterise sub-optimal prescribing. These criteria have also been incorporated into medication optimisation interventions and can be used as process measures in trials designed to assess the effectiveness of these interventions. This chapter provides an overview of the problem of sub-optimal prescribing and its facets, how this can be measured and defined, factors that contribute to sub-optimal prescribing and the impact it can have on patients and the health system. Lastly, it outlines approaches to optimising medicines and interventions that have been evaluated.