Since the first description in 1989 of CD4‐Fc‐fusion antagonists that inhibit human immune deficiency virus entry into T cells, Fc‐fusion proteins have been intensely investigated for their effectiveness to curb a range of pathologies, with several notable recent successes coming to market. These promising outcomes have stimulated the development of novel approaches to improve their efficacy and safety, while also broadening their clinical remit to other uses such as vaccines and intravenous immunoglobulin therapy. This increased attention has also led to non‐clinical applications of Fc‐fusions, such as affinity reagents in microarray devices. Here we discuss recent results and more generally applicable strategies to improve Fc‐fusion proteins for each application, with particular attention to the newer, less charted areas.