OBJECTIVES: While patients' health priorities should inform healthcare, strategies for doing so are lacking for patients with multiple conditions. We describe challenges to, and strategies that support, patients' priorities-aligned decision-making. DESIGN: Participant observation qualitative study. SETTING: Primary care and cardiology practices in Connecticut. PARTICIPANTS: Ten primary care clinicians, five cardiologists, and the Patient Priorities implementation team (four geriatricians, physician expert in clinician training, behavioral medicine expert). The patients discussed were ≥ 66 years with >3 chronic conditions and ≥10 medications or saw ≥ two specialists. EXPOSURE: Following initial training and experience in providing Patient Priorities Care, the clinicians and Patient Priorities implementation team participated in 21 case-based, group discussions (10 face-to-face;11 telephonic). Using emergent learning (i.e. learning which arises from interactions among the participants), participants discussed challenges, posed solutions, and worked together to determine how to align care options with the health priorities of 35 patients participating in the Patient Priorities Care pilot. MAIN OUTCOMES: Challenges to, and strategies for, aligning decision-making with patient's health priorities. RESULTS: Categories of challenges discussed among participants included uncertainty, complexity, and multiplicity of problems and treatments; difficulty switching to patients' priorities as the focus of decision-making; and differing perspectives between patients and clinicians, and among clinicians. Strategies identified to support patient priorities-aligned decision-making included starting with one thing that matters most to each patient; conducting serial trials of starting, stopping, or continuing interventions; focusing on function (i.e. achieving patient's desired activities) rather than eliminating symptoms; basing communications, decision-making, and effectiveness on patients' priorities not solely on diseases; and negotiating shared decisions when there are differences in perspectives. CONCLUSIONS: The discrete set of challenges encountered and the implementable strategies identified suggest that patient priorities-aligned decision-making in the care of patients with multiple chronic conditions is feasible, albeit complicated. Findings require replication in additional settings and determination of their effect on patient outcomes.