The present mini-review highlights the recent developments on different classes of synthetic hybrids of natural and/or unnatural bioactive compounds, the utilization of which is very promising, as distinct features of each component can be hybridized and their properties leveraged. Particular stress is put on the respective mode of action and the corresponding rationale behind covalent combinations of various bioactive agents to increase their therapeutic potential, facilitate their administration, to reduce harmful side effects and/or to overcome the problem of multi-drug resistance. This rather recent approach has already found applications in the development of new anti-cancer, anti-Alzheimer, anti-malaria, anti-microbial therapeutics and other novel compounds with unprecedented bioactivity.