In this talk, I will comment on the employment of the organofluorine chemistry as a tool to modulate the properties of drug-like molecules. I will particularly focus on the advent of the latest polyfluorinated groups, such as SF5, and the potential that they harbor in becoming future mainstream functionalities in medicinal chemistry. The second part of the talk will extend towards the use of small-molecule-based chemical probes for PET and fluorescence imaging as means of targeting voltage-gated calcium channels.