Chemical sensors play an important role in our understanding of chemical and biological systems, providing sensitive and rapid detection of a variety of substrates. Array-based sensing approaches avoid the ongoing challenge of designing and synthesizing selective receptors for particular analytes, a labor-intensive process that can frustrate the development of sensors. Instead, cross-reactive sensor arrays utilize multiple sensing elements that interact uniquely with each analyte and produce a distinct pattern of responses, enabling identification. To date, there are a variety of strategies both to gain cross-reactivity and diversity of sensors required for array-based sensing, and to broaden the scope of analytes for detection. Sensor arrays constructed using macromolecular components, such as polymers and nanoparticles, offer an attractive route to the discrimination of multiple, similar analytes, particularly within the context of biological sensing, where recognition over large areas is often required. Here, we focus on macromolecular sensing arrays underpinned by optical detection methods, which can enable rapid, sensitive detection of a range of analytes. We discuss the current state-ofthe art and explore the challenges to be overcome in translating exciting scientific advances to applications beyond the laboratory.