The last years have brought about unprecedented breakthroughs and discoveries in high-energy astrophysics. Most of them are related to transient phenomena and involve an increasing number of cosmic messengers ranging now from radiation across the full electromagnetic spectrum, to high-energy neutrino and gravitational waves. Due to their high sensitivity and increasingly optimized response to transient phenomena, high-energy gamma-ray observatories are playing a major role in this new field of time-domain and multi-messenger astrophysics at the highest energies. In this colloquium I will review some of the recent highlights involving transient multi-messenger phenomena with a focus on studies using Imaging Atmospheric Cherenkov Telescopes. I will present current state-of-the-art target-of-opportunity observations searching for high-energy gamma-ray emission from a variety of sources including gamma-ray bursts, gravitational waves, high-energy neutrinos and Fast Radio Bursts.