Notwithstanding variation in institutional missions, two-year colleges are the gateway to postsecondary education for the majority of college and university students in this country. As institutions of choice for many and institutions of necessity for others, two-year institutions are constantly challenged to meet the rapidly changing needs of diverse constituencies and multiple stakeholders. While two-year colleges often pride themselves in being uniquely positioned to respond to the changing needs of their communities, bringing about major change and innovation remains a formidable challenge. Nested in this context, this article addresses the following question: What strategies, under what conditions, are most promising with respect to successfully bringing about change and innovation in two-year colleges in the Midwest? Particular attention is given to change and innovation strategies implemented in emerging regional partnerships. This article is composed of four parts. The authors begin by reviewing the major models advanced in the literature on academic change. Next, they examine which of these models seem most promising for application in two-year colleges. They then advance a holistic framework, one that incorporates all of these models, as a heuristic for initiating and implementing major change in two-year colleges. Finally, drawing on the models nested within this overarching framework, they identify various change strategies associated with each of the four quadrants that comprise their model, followed by a brief description of a change effort that exemplifies the strategies associated with the respective quadrant. (Contains 1 figure and 1 footnote.)