This article presents a framework to analyze knowledge work in the changing context of new ways of working. Knowledge work increasingly takes place as collaboration from different and changing workplaces due to mobility, multilocational, and geographical distribution of participants. We define the framework based on five key factors that pose challenges to the performance and productivity of knowledge work performed in distributed teams. The framework extends and integrates traditional performance models of task, team structure, and work process, with context factors like workplace, organization policy, and information and communication technology (ICT) infrastructure. The framework is applied in a qualitative comparative cross-case analysis to eight globally distributed teams in two Fortune 100 high-tech companies. We conclude with a series of specific challenges for each factor when studying distributed knowledge work. It is shown that due to changing contexts knowledge workers, teams, and organizations need to constantly adapt, readjust, and realign according to the five factors.