The conversion of native peptides and proteins into amyloid aggregates is a hallmark of over 50 human disorders, including Alzheimer’s and Parkinson’s diseases. Increasing evidence implicates misfolded protein oligomers produced during the amyloid formation process as the primary cytotoxic agents in many of these devastating conditions. In this review, we analyze the processes by which oligomers are formed, their structures and physicochemical properties, and population dynamics and the mechanisms of their cytotoxicity. We then focus on drug discovery strategies that target oligomer formation and the ability of oligomers to disrupt cell physiology and trigger degenerative processes.