The dynamics of the Sicily Channel and southern Tyrrhenian Sea is highly influenced by the seasonal variability of the Mediterranean basin-wide circulation, by the interannual variability of the numerous mesoscale structures present in the Channel, and by the decadal variability of the adjacent Ionian Sea. In the present study, all these aspects are investigated using in-situ (Lagrangian drifter trajectories and float profiles) and satellite data (Absolute Dynamic Topography, Sea Level Anomaly, Sea Surface Temperature, wind products) over the period 1993-2018. The availability of long time series of data and of high resolution multi-sensor currents (derived from the merging of the satellite geostrophic currents and Sea Surface Temperature), allow us to add new details on the sub-basin and mesoscale features and on their driving mechanisms and to improve the recent results obtained by numerical model simulations. The combined use of all these datasets leads to overcome the main intrinsic limitations of each of them, provide the temporal variability of the main mesoscale structures, detect new permanent eddies not yet described in literature, describe how the external and/or internal forcings can modulate the strength of the mesoscale seasonal and interannual variability. The vertical structures and the hydrological characteristics of these mesoscale eddies are eventually delineated using the Argo float profiles when they are entrapped in these structures.