We propose a methodology for making optimal registration decisions during 3D volume reconstruction in terms of (a) anticipated accuracy of aligned images, (b) uncertainty of obtained results during the registration process, (c) algorithmic repeatability of alignment procedure, and (d) computational requirements. We researched and developed a web-enabled, web services based, data-driven, registration decision support system. The registration decisions include (1) image spatial size (image sub-area or entire image), (2) transformation model (e.g., rigid, affine or elastic), (3) invariant registration feature (intensity, morphology or a sequential combination of the two), (4) automation level (manual, semi-automated, or fully-automated), (5) evaluations of registration results (multiple metrics and methods for establishing ground truth), and (6) assessment of resources (computational resources and human expertise, geographically local or distributed). Our goal is to provide mechanisms for evaluating the tradeoffs of each registration decision in terms of the aforementioned impacts. First, we present a medical registration methodology for making registration decisions that lead to registration results with well-understood accuracy, uncertainty, consistency and computational complexity characteristics. Second, we have built software tools that enable geographically distributed researchers to optimize their data-driven registration decisions by using web services and supercomputing resources. The support developed for registration decisions about 3D volume reconstruction is available to the general community with the access to the NCSA supercomputing resources. We illustrate performance by considering 3D volume reconstruction of blood vessels in histological sections of uveal melanoma from serial fluorescent labeled paraffin sections labeled with antibodies to CD34 and laminin. The specimens are studied by fluorescence confocal laser scanning microscopy (CLSM) images.