CHDI is a not-for-profit drug discovery organisation that is exclusively dedicated to accelerating the development of therapeutics that slow the progression of Huntington's disease (HD). Over the past decade we have created a large and diverse portfolio of projects to fulfil this mission. Each individual project is predicated on an evidence-based mechanistic hypothesis as to why pharmacological intervention at a particular biological target is predicted to have a beneficial effect on HD pathophysiology, and is designed to identify a proof-of-concept molecule for in vivo testing as quickly as possible. The particular therapeutic modality for each project is selected based on its relative merits, and to date have included small molecules, antibodies, antisense oligonucleotides, siRNAs, and virally-delivered genetic payloads. Our non-clinical scientists strive to optimise the drug-like properties of the candidate molecules to maximise their chances of success in the clinic. Ultimately, we believe that the target-product-profile for a drug must be informed by clinical data from the target population. Early clinical studies may be required to inform one or more of: dose (amount, frequency, and route), patient selection (disease stage), compound exposure (pharmacokinetics), target occupancy and engagement (pharmacodynamics), biological effect, safety markers, and outcomes that will be used in the larger later-stage efficacy trials. As the portfolio matures and migrates away from historical nutraceuticals and repurposed drugs to truly new-chemical-entities, we consider these issues critical to our collective success. CHDI hopes to partner with the impressive capabilities that the EHDN has built to carry out the clinical aspects of our efforts. An overview of the current programs, along with their challenges and opportunities will be presented.