Pivot Park Screening Centre (PPSC) has expanded its ultra-High Throughput screening (uHTS) platform with the integration of RapifleX Maldi PharmaPulse® (Bruker AG), along with Cell-Bio Well Vario system (Analytik Jena AG) for fully automated label-free mass spectrometry (MS)-based uHTS. Here, we reflect on the challenges and lessons learned during the integration, illustrate results from our first MS-based uHTS and reflect on the applications and future developments towards affinity-selection and cell-based MALDI MS assays.