Ionospheric irregularities can adversely affect the performance of Global Navigation Satellite System (GNSS). However, this opens the possibility of using GNSS as an effective ionospheric remote sensing tool. Despite ionospheric monitoring has been undertaken for decades, these irregularities in multiple spatial and temporal scales are still not fully understood. This paper reviews Virginia Tech’s recent studies on multi-scale ionospheric irregularities using ground-based and space-based GNSS observations. First, the relevant background of ionospheric irregularities and their impact on GNSS signals is reviewed. Next, three topics of ground-based observations of ionospheric irregularities for which GNSS and other ground-based techniques are used simultaneously are reviewed. Both passive and active measurements in high-latitude regions are covered. Modelling and observations in mid-latitude regions are considered as well. Emphasis is placed on the increased capability of assessing the multi-scale nature of ionospheric irregularities using other traditional techniques (e.g., radar, magnetometer, high frequency receivers) as well as GNSS observations (e.g., Total-Electron-Content or TEC, scintillation). Besides ground-based observations, recent advances in GNSS space-based ionospheric measurements are briefly reviewed. Finally, a new space-based ionospheric observation technique using GNSS-based spacecraft formation flying and a differential TEC method is demonstrated using the newly developed Virginia Tech Formation Flying Testbed (VTFFTB). Based on multi-constellation multi-band GNSS, the VTFFTB has been developed into a hardware-in-the-loop simulation testbed with external high-fidelity global ionospheric model(s) for 3-satellite formation flying, which can potentially be used for new multi-scale ionospheric measurement mission design.