Covalent inhibitors are recognized as an important component in drug discovery and therapeutics. Since the first appearance of covalent inhibitors in the late 18th century, the field has advanced significantly and currently about 30% of the marketed drugs are covalent inhibitors. The numerous advantages of covalent inhibitors are counteracting the initial concerns regarding potential off-target toxicity. Thus, continuous research, especially for cancer targets is reported. The aim of this review is to provide a short historic overview and focus on recently developed covalent inhibitors (2011–2019), including structural aspects and examples on challenging targets.