Since the discovery of SARS-CoV-2 in late 2019, intense research efforts on an unprecedented scale have focused on the study of viral entry mechanisms and adaptive immunity. While the identification of ACE2 and other co-receptors have elucidated the molecular and structural basis for viral entry, the pathobiological mechanisms of SARS-CoV-2 in human tissues are less understood. The recent advances in bioengineering have opened opportunities for the use of organotypic human tissue models to investigate host-virus interactions and test antiviral drug candidates in a physiological context. While it is too early to accurately quantify the added value of these systems compared to conventional cell systems, it can be assumed that these advanced 3D models contribute towards improved result translation. This mini-review summarizes recent work to study SARS-CoV-2 infection in human 3D tissue models with an emphasis on the pharmacological tools that have been developed to understand and prevent viral entry and replication.