In this chapter, we aim to summarize the most important and most relevant computational medicinal chemistry approaches used in the discovery of GPCR ligands. We introduce the applied computational methods and resources through the most frequent tasks/problems researchers encounter during computational studies targeting GPCRs. The chapter starts from structure preparation and goes through the steps of an imaginary comprehensive computational study tackling the questions like selectivity, functional selectivity and biased signaling. The spread of this chapter does not allow to dive deeply into the technical details of the specific methods, rather we refer the reader to more specific reviews. In the text, we mainly highlight the successful applications of the most wide-spread methods available while pointing out potential drawbacks as well.