Osteoarthritis (OA) is a debilitating and degenerative disease of the joint characterized by erosion of articular cartilage. No disease modifying OA drugs (DMOADs) are approved, and cell-based therapies are limited. The differentiation of human induced pluripotent stem cells (hiPSCs) to prescribed cell fates enables the engineering of patient-specific tissue types, such as hyaline articular cartilage, for applications in regenerative medicine, disease modeling, and drug screening. In many cases, however, these differentiation approaches are poorly controlled and generate heterogeneous cell populations. In this dissertation, we demonstrate utility of hiPSCs for efficient chondrogenesis and OA disease modeling. Using a standardized differentiation approach, we demonstrate cartilaginous matrix production in multiple hiPSC lines using a robust and reproducible differentiation protocol. To purify chondroprogenitors produced by this protocol, we engineered a COL2A1-GFP knock-in reporter hiPSC line by CRISPR-Cas9 genome editing. Purified COL2A1-GFPhigh chondroprogenitors demonstrated an improved chondrogenic capacity compared to unselected populations, improved matrix homogeneity, and reduced variability between tissues. We next demonstrated the ability of the system to serve as a high-throughput system for arthritis disease modeling using cytokine stimuli. Using the cytokine stimuli TNF-alpha and IL1alpha, we observed that engineered tissue exhibits a dose-dependent degenerative response. COL2A1 reporter activity showed a strong correlation with GAG loss, emphasizing the utility of the reporter as a read-out for drug screening applications. Step-wise directed chondrogenic differentiation of hiPSCs using small molecules and growth factors is a heterogeneous process that exhibits considerable heterogeneity and cell line – cell line variability, which may limit its clinical application. To overcome this variability, we sought to identify the transcription factors that might drive chondrogenic commitment from the pluripotent state. To this end, we applied our chondrogenic differentiation platform to a CRISPR activation (CRISPRa) screen to identify prochondrogenic transcription factors. Taken together, these studies describe the generation of a high-throughput system for chondrogenesis and its application for screens and arthritis disease modeling. Future applications of this platform may be useful for identifying pathways driving cartilage regeneration and novel therapeutics for arthritis.