In canonWhen Chiyo and Sakaki first meet, Chiyo is afraid of Sakaki because she thinks she seems scary and at one point suspects Sakaki may have got in a fist fight because of her bandaged hand which was actually injured because of a cat bite. Though Chiyo gradually discovers Sakaki's true nature and that they have some interests in common, such as stuffed animals. Sakaki is also very fond of Chiyo's dog Tadakichi-san whom she met when she was on a walk and ran into Chiyo.
The two of them live in the same neighbourhood and once they get to know each other, they become friends. As explained in the "A Day In Chiyo-chan's Life" part, they often have company on the way to school. They both think that the world misjudges them based on their appearance – Sakaki is perceived as mysterious or cool because of her height and imposing air while Chiyo is always seen as cute. Though Chiyo would rather be met with more respect, while Sakaki would prefer to be shorter so that her soft side would seem more natural to others. They are both kind and polite personality-wise.One crucial point in their relationship was when Kamineko became the new leader of the neighbourhood cats and attempted to attack Sakaki and Chiyo, who were on their way from school, all at once. Maya, the cat Sakaki met on Iriomote Island, returned and rescued the two of them, whereafter Chiyo took him to the veterinarian Tadakichi-san was usually taken to, making sure that he would be fine after he passed out following the cats' attack. Chiyo then let Maya stay at her house until Sakaki would graduate from high school and get her own apartment where Maya would be able to live.
While not the most popular pairing, the two of them are frequently seen together in fan art and official merchandise for the series, probably because of the contrast between them. There are also a number of fanfics and AMVs related to the pairing online. According to TV Tropes, the reason they interact so often is because they bring out each other's positive qualities.
The relationship they share is very similar to that shared by Lucky Star characters Yutaka and Minami. Both Chiyo and Yutaka are very short (although Yutaka is actually older, just unusually short), and Minami and Sakaki are both tall and come off as intimidating (though Minami is not the tallest, and she is completely flat-chested as opposed to Sakaki's large breats). Also unlike SakaChiyo, there is much more evidence of a romance between Yutaka and Minami, to the point that another character, Hiyori Tamura, draws manga featuring the two. Yutaka and Minami also frequently appear together in fanart and merchandise, and are considered the second-most popular pairing in the series (the first being the widely-popular pairing between Konata and Kagami, who themselves have a very similar relationship to Tomo and Yomi).