Hospitalization in the pediatric intensive care unit (PICU) is stressful for families and disruptive for their normal lives. As new technology has become available, the number of children requiring prolonged stays in the PICU has increased. This mixed methods study explored stress in families whose children were hospitalized in the PICU for more than one week, collecting data one to two weeks after admission, then four to five weeks later. The purpose was to describe sources of stress for families whose children require extended hospitalization in the PICU and explore how sources of stress change over time. Data collection included semi-structured interviews and completion of the Family Inventory of Life Events (McCubbin, Thompson & McCubbin, 1996) and Family System Stressor Strength Inventory (Berkey & Hanson, 1991) at each time point. Nine parents of eight children participated in the first phase of data collection; two mothers participated in the second phase. Data analysis revealed the following themes related to Aim 1 (sources of stress): separation, not knowing, child’s illness and distress, care and caring, emotional stress, physical stress, job and financial stress, and what we’ve been through before. Themes related to Aim 2 (change over time) were: stress builds, and stress decreases as the unknowns become known. Analysis of Time 2 data revealed similarities in sources of stress compared to Time 1, but there was a shift in the relative priority and contribution that each stressor made to the overall perception of stress as hospitalization became prolonged and the child’s condition improved; participants reported aspects of care and caring as most important at this point. A new subtheme in the original care and caring theme was also identified: considering the child’s entire picture. Findings demonstrated sources of stress directly related to the child’s acute illness as well as stress resulting from the child’s hospitalization and ongoing healthcare needs, all of which contributed to the perception of family stress. Over time, stress was compounded and there was a shift from the primary stressors of unknowns and separation of the family to stressors related to the care and caring provided by the team.