CMOS chips are increasingly used for direct sensing and interfacing with fluidic and biological systems. CMOS circuits for sample acquisition, signal processing, and readout have been integrated with various sensors to form complex biosystems-on-chip. However, distinct and vexing technical challenges arise from the disparate requirements of biosensors and integrated circuits. From the perspective of integrated circuits, direct CMOS biosensing creates challenges in: packaging; materials selection; physical design constraints due to topography; MEMS post-processing of CMOS die; energy and power limitations; and transfer and processing of signals. From the perspective of biology, direct CMOS biosensing creates challenges in: fluidic integration; electrochemical effects; biocompatibility; environmental maintenance and surface treatments to support cell health and function; and optical assessment of opaque samples. We will describe these challenges and review lessons learned.